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Would you like to change to the United States site? The illustrations, the chapter summaries with relevant information, and the case studies are all particularly useful for the targeted readers. The book is well designed and manages to convey the general concepts of the various aspects of infectious diseases without overwhelming the reader with too much information… recommended for students, trainees, or physicians who desire a well-illustrated textbook that is easy to read and that addresses the basic aspects of infectious disease.

The study of infectious diseases has undergone major changes since its infancy when it was largely a documentation of epidemics. It has now evolved into a dynamic phenomenon involving the ecology of the infectious agent, pathogenesis in the host, reservoirs and vetors, as well as the complex mechanisms concerned in the spread of infection and the extent to which this spread occurs.

Rapid globalization has led to unprecedented interest in infectious diseases worldwide and their effect on complex population dynamics including migration, famine, fire, war, and terrorism. It is now essential for public health officials to understand the basic science behind infectious disease and, likewise, students studying ID must have a broader understanding of the implications of infectious disease in a public health context as well as clinical presentation and prevention.

The clear demand for an integrated approach has led to the publication of this text. Check out the student companion site at www. View Student Companion Site. He completed all his specialist training in the UK and has worked and taught students in London, Hong Kong, and Singapore. She completed her training from University College and other affiliated hospitals in London.

Her current position involves the diagnosis and management of infection in the community and the hospital and includes infection prevention and control. Host defence versus microbial pathogenesis and the mechanisms of microbial escape N. Shetty, E. Aarons, J. Infections in the immunocompromised host HIV, solid organ transplant recipients, haematological malignancies D.

Mack, N. Tang, P. The book is well designed and manages to convey the general concepts of the various aspects of infectious diseases without overwhelming. Undetected location. Distinct from other animal models, rabbits clear the infection and become protected from reinfection with the same Borrelia strain but they are not protected when another B. As such, rabbits do not serve as good model for persistence, but can serve as models of EM development and other aspects of early infection as well as the study of protective immunity.

However, the lack of tools for study in rabbits places limitations on the use of this model. Non-human primates : Studies in rhesus macaques and baboons demonstrated that these non-human primates NHP present with EM and develop disseminated infection in a manner that is hypothesized to mirror that of humans, due to their genetic relatedness Hefty et al. For this reason, NHPs are likely the most relevant animal model for Lyme disease.

In many, but not all, instances, cultivation of B. However, other experimental metrics suggest that they continue to be present in a persistent state. Specifically, B. More recent studies detected B. While the earlier studies in NHP used a more virulent strain of B. The lack of clinical manifestations of disease in these NHP must be considered a limitation for this Lyme disease model. In immunosuppressed NHPs, the number of spirochetes in tissues increases substantially Bai et al. There are also signs of inflammation observed in cardiac and neural tissues, respectively.

However, the relevance of chemically-immunosuppressed NHPs as a model of natural disease in immunocompetent humans is debatable. Furthermore, the limited availability and cost of NHPs, and the ethical considerations of their use, are substantial drawbacks to their use as an infection model. Most individuals who present with classic early symptoms of Lyme disease, for example EM accompanied with flu-like illness, will clear the infection if treated immediately with antibiotics.

However, not all infected humans develop an EM inflammatory response, or the EM may not be noticed. Unless treated within the first few weeks of infection, B. Treatment at this stage can also be successful but may require extended antibiotic treatment. The underlying cause of ongoing disease is unknown and subject of intense discussion. Another subset of patients, including some who initially received antibiotic treatment, develop a persistent condition that is more challenging to treat effectively.

We lack an understanding of why humans respond differently to the infection. A more complete understanding of these differences could inform the development of more patient-specific and distinct treatment regimens. Detailed studies on Lyme borreliosis in humans are limited for obvious reasons. While studies in dogs and NHP can provide surrogates for diseases seen in humans, particularly neuroborreliosis, experimental models using mice are the mainstay in basic science given their ease of use and cost.

However, as indicated, there are significant distinctions between human and mouse infection with B. The most prominent difference is their overall tolerance to infection and absence of disease manifestations, similar to that seen in naturally infected rodent species. This includes the absence of EM lesions, mild-to-absent inflammatory conditions of the heart and joints in most strains, and a general lack of neurological infectivity.

The latter might be a result of reduced levels of connective tissue in the brain of small vertebrates relative to larger ones, although this possibility has not been formally studied. Thus, while mice will remain a critical species for studies that reveal the function of B. As outlined above, ample evidence demonstrates that B. Most patients suffering from acute symptoms of B.

However, the prevalence of subclinical infection of B. The concept and findings of persistence of B. Both in vitro and in vivo evidence has been presented to suggest that B. It remains to be determined whether borrelial persistence following antibiotic treatment is a genetically encoded characteristic, or is due to environmental conditions such as osmotic shock or inadequate distribution of antibiotics. Studies that distinguish between these potential mechanisms should be considered a high-priority for future research into the mechanisms of Borrelia persistence and the clinical presentations of ongoing signs and symptoms of Lyme disease.

Studies from the Lewis Sharma et al. These morphological changes were associated with increased tolerance to antibiotic treatments in vitro. In addition to finding spirochete DNA, evidence for antibiotic-resistant B. Consistent across all studies, cultures established with tissues from antibiotic treated animals remained negative for B. It should be noted that in some cases, cultured human specimens were B.

This is because viable spirochetes could not be retrieved from the antibiotic treated host mouse, the tick that fed on the host mouse, and the mice exposed to the ticks. This lack of retrieval has prevented the demonstration of active infection reviewed in Shapiro, While this is accurate, no plausible explanation has been put forward that could account for the persistence and transfer of Borrelia genetic material DNA from an infected and antibiotic-treated mouse to a tick that fed on that mouse and the retrieval of the DNA in immunodeficient mice exposed to the DNA-containing ticks.

Further work is needed to resolve this issue. One recent study put forward evidence for recrudescent infection of B. That study reported on the resurgence of non-culturable B. In that study, PCR analysis for DNA was negative for nearly all tissues for cohorts of mice three and eight months after antibiotic treatment, but was positive for most tissues 12 months after infection. Data were confirmed by xenodiagnoses, demonstrating the presence of DNA and protein in ticks fed upon those mice. Unfortunately, the month time point was the last analyzed.

In a recent study, non-human primates were treated for 28 days with doxycycline, four months after their initial infection with B. Seven to nine months post-treatment, intact and viable RNA-transcribing spirochetes were recovered by xenodiagnosis and through the use of an in vivo culture system. These organisms were of comparable viability to those recovered from untreated primates Embers et al. See the discussion below for details regarding B. Studies of additional antibiotics, used alone, in combination, or different treatment regimens are warranted, as are further studies into the nature of potential residual spirochetes present in tissues of infected and then antibiotic treated animals.

The zoonotic lifecycle associated with Lyme disease is very complex. Since the Lyme disease spirochete is not passed through eggs from infected female Ixodes ticks, the larval ticks must acquire B. Larval acquisition of B. After molting from larva to nymph, the tick seeks to feed on a new host. This can result in transmission of B. During transmission of B. These tick saliva proteins alter both innate and adaptive immune functions by promoting vasodilation and altering platelet aggregation, coagulation, inhibiting complement, skewing neutrophil function, and impairing T and B cell responses Couvreur et al.

During the blood meal, as B. These enable B. This includes changes in the proteins expressed on the outer membrane of B. How the spirochete senses the tick feeding is not fully understood, nor are the regulatory pathways known that coordinate repression of tick-specific factors while enhancing production of vertebrate-specific factors. Even though large numbers of proteins are known that are produced coordinately, it is important to emphasize that we know very little about the function of most of these proteins.

Given the extent and energy that B. More detail about the change at the transcriptional and post-transcriptional level is provided below. After initial infection into the skin, B. They are actively motile at this point. They avoid killing by innate immune responses, such as the alternative pathway of complement. There is no evidence to suggest that B. Instead the spirochete coats itself with host enzymes and other proteins that facilitate dissemination.

See Appendix 1 for more detail. Invasion into connective tissues results in further spread of the infection to more distant lymph nodes, joints, cardiac, spleen, and bladder tissues, as well as skin sites. Proteins derived from B. Despite these significant advances, we still do not understand much of the molecular details regarding the spread of B. Additional studies are needed to determine the mechanisms underlying the ability of B. Gene expression and protein production. Pathogens utilize genetic regulatory mechanisms to adapt to the changing environments they encounter during infection to ensure their survival.

Nevertheless, there are still gaps in our knowledge base regarding the schemes that regulate gene expression and protein production in B. For example, B. Both systems require soluble regulatory proteins, known as response regulators, and membrane bound histidine kinases. The two response regulators encoded by B. However, the signal that is perceived in either system is not known.

Numerous other regulatory proteins have been identified in B. With this paucity of information comes the need to further characterize these processes. In addition to conventional transcriptional regulation, the presence of small, non-coding RNAs, or sRNAs, have been identified in nearly every bacterium examined, including B.

Recent data indicates that B. The binding of sRNA to specific mRNA occurs via specific sequence recognition and either enhances or inhibits translation to proteins and, as such, represents a post-transcriptional form of regulation. Other sRNAs may bind and sequester regulatory proteins, thereby preventing the proteins from interacting with other target sites. How sRNAs fit into the pathogenic potential of B.

They also bind specifically to other mRNAs, and appear to control translation of numerous proteins. Despite our lack of knowledge about the regulatory mechanisms operative in B. A number of the signals likely to be in play here for example, temperature, pH, O2 and CO2 levels, bacterial replication rates, and nutrients have been analyzed in vitro Arnold et al. Recently, a comparison of total transcript profiles were compared between in vitro grown B. While one might predict that the tick-associated transcript profiles would be similar, the fed larvae and nymphs were vastly different and looked significantly different than in vitro mammalian grown B.

Most striking was the differences observed with the in vivo adapted profile. Several genes that were highly expressed in the tick or in culture were turned off in the mammalian host adapted state. Many other genes are shut down in fed larvae only and those are highly expressed during mammalian infection Iyer et al.

From this analysis it is clear that B. These changes are undoubtedly critical for transmission, survival within the tick, and for the establishment and maintenance of mammalian infection. Studies that address these events at the molecular level need to be continued and expanded upon. Among other outcomes, such studies can reveal new targets for improved therapies to prevent and cure human infection. Antigenic variation. The antigenically variable surface protein VlsE is essential for persistent infection of vertebrates.


Infectious B. This system can yield up to VlsE variants. This level of variability means that each B.

The crystal structure of VlsE showed that the variable domains, which are subjected to the recombination events described, map to the surface exposed face of VlsE Eicken et al. A much less immunogenic part of the VlsE protein, that does not undergo antigenic changes, is IR6 or C6. While this antigen is often used in the serological evaluation of patients for its stable expression, the antigen maps to an internal structure within VlsE Eicken et al. The mechanisms that control the ability to vlsE to undergo variation at only the critical time of mammalian infection remain to be elucidated fully.

Production of the VlsE protein, and transcription of its gene, is tightly regulated by B. Because of its importance in persistence, identifying and targeting the signal s required for host specific recombination in vlsE , and for activation of VlsE production, would provide important insights into how this critical B. Resistance to Complement Killing. The complement cascade is key in the rapid, innate host defense, by detecting and clearing foreign invaders. For B. Without complement resistance mechanisms at this stage of their lifecycle, B. Several Borrelia proteins mediate resistance to the alternative pathway of complement activation.

All of the aforementioned borrelial proteins bind to the complement component factor H or factor H-like protein 1, which prevent activation of the alternative pathway of complement. Such killing does not require antibodies or any other factor. For that reason, B. C4BP binding to both B. C4BP is another soluble regulator in the complex complement scheme, and it affects a step common to the classical and lectin pathways of complement activation.

Infectious Disease: Pathogenesis, Prevention and Case Studies

Binding of C4BP to the surface of pathogens alters the stability of the classical convertase that is required for complement activation. In practice, the binding of factor H and C4BP together could render a foreign system resistant to all complement-dependent killing, which, in theory, could be mediated by only two encoded proteins. However, extracellular pathogens have evolved numerous back up strategies that ensure that the loss of any one gene does not put the organism at a selective disadvantage.

The numerous borrelial factor H binding proteins illustrate this point. By analogy with other extracellular pathogens for example, Staphylococcus aureus that have many redundant complement neutralizing activities, it is likely that B. Recently, an inhibitor that is specific for the classical pathway of complement activation was identified in B. The classical pathway, in general, works by engaging the C1 complement complex with antibody-bound antigen.

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The interaction of C1 with the antigen-antibody complex results in complement activation and killing of a targeted cell. Somewhat surprisingly, the B. BBK32 is a bipartite molecule with a structurally unordered amino terminal half that attains a stable structure when it binds to fibronectin Kim et al. The carboxy C- -terminal half is highly ordered but had no known function.

Thus, it is possible that BBK32 may serve to minimize complement-dependent, antibody-dependent killing of B. As discussed above, upon its entry into the mammalian host, B. However, tick salivary proteins play a role in suppressing the host immune system as long as the tick vector is attached. Most of the information we have about these processes come from experimental infection in mice. Predominantly, infection with B. The induction of Type I IFN is surprising, given that the known protective functions of these cytokines are usually associated with viral and intracellular bacterial infection.

Further work is required to determine whether the induction of Type I IFN helps the control of infection, or whether it might be driving some observed immune pathology Miller, Ma, Bian, et al. Interpretation of studies conducted in vitro are complicated by the fact that culture-grown B.

However, the fact that mice lacking the innate adaptor molecule MyD88 show much higher Borrelia- loads than mice expressing this protein Bolz et al. However, given that even fully immunocompetent mice cannot clear the infection, the data suggest that while the adaptive immune system is activated, it is not fully functional. As discussed above, serum transfer studies with serum from infected mice have demonstrated that antibodies can protect from a challenge infection, even though the antibodies are unable to clear the infection in the host from which they were derived.

Another puzzling aspect of the antibody response is that the protective capacity of the serum seems initially to increase with ongoing infection, i. However, by about months after infection, this protective capacity reversed, such that sera from mice infected for about 1 year were less protective than those taken from day 60 of infection.

Although it is currently not possible to measure all antibodies generated against B. These studies suggest dramatic changes in the functionality of the developing antibodies. The mechanism underlying these change is unknown, but likely important for the understanding of immune protection and immune evasion by B. Immune sera from T cell-deficient mice, but not B cell-deficient mice, were shown to be protective against challenge McKisic et al. One of the few, but notable differences of T cell deficient mice compared to wild type controls is a significant reduction in class switch recombination from IgM to IgG, suggesting that T cells do participate in the B cell response to B.

Patients with early Lyme disease have increased levels of both B. This is followed by rising levels of total serum IgG, including antibody to an expanding array of B. Experimentally infected mice also have a significant rise in both specific and non-specific IgM and IgG, as well as an increase in peripheral lymph node B cell numbers Yang et al. While these earlier studies described some of the induced antibody responses as non-specific, as discussed B. Indeed, experimental studies in mice suggested the induction of mostly Borrelia -specific antibodies Tunev et al.

As infection proceeds in humans, IgM titers decline, but there is a curious persistence of IgM reactivity for months to years against a small number of proteins in the range of and kDa on immunoblots made from B. Antibiotic-treated humans Nowakowski et al. Indeed, recent studies in mice showed a lack of memory B cell and long-lived plasma cell induction following B. This reduction in immune response effectiveness was seen also when B. The mechanisms Borrelia employs to suppress effective long-term immunity remain unknown and this constitutes a significant gap in our understanding of Borrelia -pathogenesis and disease.

The discussed changes in B. Antigenic variation is another process that likely reduces effectiveness of antibodies against B. As outlined above in detail, the variable surface antigen E vlsE locus is a major immunodominant surface protein of B. The lack of vlsE variation was shown to result in the rapid clearance of B. Occupation of specific sites in the mammalian body.

Analyses of infected mammals shows a predilection of B. The nature of those host tissues may also impede distribution of antibiotics during treatment. VlsE and other proteins as protective shields. The VlsE protein forms an elongated structure, with a spreading domain at the end away from the bacterial surface it may be said to resemble a tree, with a narrow trunk and spreading foliage up high. It is possible that VlsE contributes to B. Another possibility is that some of the B.

Neither of these hypotheses have been examined in detail. Formation of altered forms of B. However, there is significant concern that the forms observed under in vitro environments are not relevant to mammalian infection. The absence of the regulatory protein RpoS resulted in a higher frequency of round body formation, but this distinct morphotype was seen even for the wild type parent strain, albeit at lower frequency Dunham-Ems et al.

Interestingly, these rounded, enlarged forms of B. Studies to assess whether these forms can be visualized during experimental mammalian infection may provide important insight into this unique adaptive form. If they exist, detection of alternate forms, coupled with reversion to normally shaped spirochetes, would suggest that B. Evidence for intracellular residence An important aspect of persistent infection is the ability of the pathogen to initially evade complete sterilization by innate immunity and then to survive the subsequent adaptive immune response.

In the case of B. However, despite these responses, the spirochete is able to persist. These observations led to a hypothesis that B. Whether or not such an event occurs in vivo is not known and provides another important gap in our knowledge that has potential implications for the treatment of patients, since not all antibiotics effectively cross cell membranes. The tissue models, discussed above, which showed some invasion of B.

The finding of B. While detailed and extensive searches for direct evidence of B. The gold standard is culture. Other direct detection methods include detection of B. As it is with other infectious agents, the potential that positive culture or PCR results reflect inadvertent laboratory contamination must be carefully considered Fallon et al. PCR evidence of B. Microscopy has also been used to document the presence of B. Evidence of persistent B. Published cases of culture-proven treatment failure have been relatively rare.

However, they do exist despite the lack of available culture tests for clinical use. Notable were the reports by Hunfeld Hunfeld et al. Five of these 19 cases were studied in great depth; none reported a second tick bite, all took their medication as prescribed amoxicillin for 14 days 1 , ceftriaxone for 14 days 1 , cefuroxime for 14 days 2 , or azithromycin for 6 days 1.

Culture results from four of the five patients revealed the same genospecies before and after treatment, suggesting these were persistent infections rather than reinfections. Reinfection in endemic areas is not rare. Thus, symptoms or signs that emerge months to years later may be due to re-infection rather than the recrudescence of an old infection and culture, PCR and microscopy cannot distinguish between the two.

Therefore, in these instances, supplemental clinical information regarding the nature of the signs and symptoms could be informative. For example, individuals presenting with another episode of an EM lesion following antibiotic treatment are likely to have a repeat infection Nadelman et al. Numerous case reports have been published demonstrating PCR evidence of persistent B. Positive PCR results in the immediate post treatment could represent debris from dead bacteria that has yet to be cleared.

However, with the exception of joints, where bacterial clearance can be substantially delayed and positive PCR results for synovial fluid or tissue samples may not reflect current infection Li et al. It should be noted that in the majority of the papers cited in the text and the appendix, the specimens that produced positive PCR results were obtained 6 or more months following antibiotic treatments, making delayed clearance a less likely explanation. Antigenic components of B. In this case report, OspA and PCR positivity were detected in the cerebrospinal fluid of a patient with seronegative neurologic Lyme disease on four occasions after separate courses of antibiotic treatment for relapsing-remitting symptoms.

As noted above, the available laboratory tools for demonstrating the presence or absence of viable B. In light of the human case evidence discussed above, the in vitro appearance of persisters in antibiotic treated cultures of B. Some B. Culture studies are easier to control for exogenous factors and they are also less expensive.

However, the relationship between findings in culture and in mammalian host are unknown, given the considerable changes B. Inhibition of the complement system and suppression of strong inflammatory responses are examples of effective evasion of innate immunity by B. Strategies for antigenic variation by B. Promote research on models of B. Research on the mechanisms inducing human disease processes induced by B.

Each animal model has unique advantages and disadvantages for understanding human disease and Borrelia persistence. Studies using these models can contribute to a deeper understanding of immune evasion and disease processes as well as host-pathogen interactions and the biology of this pathogen. However, none of the existing animal models has fully captured the clinical picture of humans suffering from the long-term consequences of neuroborreliosis and the development of such a model is needed. Another as of yet incompletely understood mechanism, is how B.

Further studies on mechanisms of B. As shown in mice, B. The lack of long-lasting responses may also explain that reinfections are common in endemic areas. Furthermore, some evidence has been provided recently to suggest that the inhibition of strong adaptive immunity during B. Whether this more general immune suppression occurs in humans should be further studied, as it may have diagnostic and treatment implications for patients who are simultaneously infected with more than one tick borne pathogen. B burgdorferi uses complex mechanisms to survive in immunocompetent mammals, including humans, seemingly even in the presence of antibiotic treatment.

More studies are urgently needed to learn how to overcome mechanisms of Borrelia persistence and its relationship to human Lyme disease. Lyme disease is a multi-system, multi-staged infection with diverse symptomology. Patients may present with a simple rash or with a multitude of symptoms and signs in either inpatient or outpatient settings. This section discusses what is currently known about the pathophysiology of Lyme disease and areas where additional knowledge is required to reduce diagnostic delays and improve patient care. The most common sign of human infection with B. EM lesions are typically annular in shape.

In the untreated, the rash will expand in size for days to weeks before clearing. Figure 1 highlights the varied appearance of EM lesions. Such errors are potentially confusing to patients and clinicians. The reasons for different rash presentations in patients are not known. Recent studies in non-human primates, however, showed that despite being infected with an identical strain, only 3 of 10 infected rhesus macaques developed erythema at the site of infection, and only 1 of the 3 could be classified as a bona fide EM lesion.

Like humans, the non-human primates used in the studies were genetically heterogeneous Embers et al. The EM lesion is a manifestation sign of the localized immune response to B. Recognition of the bacteria by the immune system leads to the recruitment of inflammatory cells and, ultimately, redness of the overlying skin. The inflammatory response continues and follows along as B. Early disseminated Lyme disease: multiple disseminated Lyme disease: multiple red lesions with dusky centers. Expanding rash with central clearing: circular red rash with central clearing that slowly expands.

The most common early manifestations of Lyme disease see Figure 2 include arthralgia joint pain , headache, myalgia muscle pain , fatigue, and fever. In many Lyme-endemic states in the US, the seasonal cycle of tick encounters is used to help doctors distinguish Lyme disease from other infectious diseases that produce similar nonspecific symptoms such as influenza and other viral infections. The majority of Lyme disease infections result from nymphal tick bites.

In the Northeast and Midwest, the seasonal peak of nymphal tick populations occurs in the late spring and early summer, when influenza and other viruses are not circulating in adult populations. However, in other areas where B. The lack of tick seasonality introduces another challenge to arriving at the correct diagnosis. Convalescent cytokine production, however, did not correlate with initial symptom types, duration of symptoms prior to treatment, or clinical evidence of spirochetal dissemination Glickstein et al.

In humans, B. The most prominent symptoms are fatigue, musculoskeletal pain, neurocognitive dysfunction, and sleep disturbances, but also include a number of other symptoms such as headache, paresthesias, and palpitations. A recently published paper identified 25 signs and symptoms in which the severity of each manifestation was significantly greater in patients with well-defined PTLDS than healthy controls Rebman et al. Figure 3. Lyme disease patients with persisting manifestations report severe symptoms. The underlying pathophysiology in patients who have persistent symptoms associated with Lyme disease, whether having had some antibiotic treatment or no prior antibiotic treatment, is poorly understood.

Pathologic studies in humans are limited. Although there are tissue-specific differences, in general, perivascular infiltrates of lymphocytes, macrophages and plasma cells are prominent. Tissue necrosis is uncommon. Early in the course of Lyme disease, a number of inflammatory correlates have been identified that could explain some of the general symptomatology Soloski et al. The diagnosis of HIV-1 infection is based on the detection of specific antibodies, antigens, or both, and many commercial kits are available. Serological tests are generally used for screening.

A major advance has been the availability of rapid HIV-1 antibody tests. These assays are easy to do and provide results in as little as 20 minutes, enabling specimen collection and proper diagnosis at the same visit. Rapid tests are important tools for surveillance, screening, and diagnosis, and can be reliably done on plasma, serum, whole blood, or saliva by health-care providers with little laboratory expertise.

The two limitations of these serological tests are detection of infection during primary infection when antibodies are absent, and in infants younger than 18 months who might bear maternal HIV-1 antibodies. In these instances direct virus detection is the only option eg, quantification of viral RNA [standard] or p24 antigen in heat denatured serum [less expensive]. Plasma viral load is widely used to monitor therapeutic success on antiretroviral treatment. These requirements pose challenges for resource-constrained settings.

The use of dried blood spot specimen has resolved some of the difficulties associated with transportation of samples needed for virological assessments. Antiretroviral treatment is the best option for longlasting viral suppression and, subsequently, for reduction of morbidity and mortality. However, current drugs do not eradicate HIV-1 infection and lifelong treatment might be needed. Fixed-dose combination tablets simplify treatment regimens by reducing the daily pill burden, and drugs with long half-lives allow once or twice daily dosing.

Eight protease inhibitors prevent the maturation of virions resulting in production of non-infectious particles. The recently approved darunavir June, is the first of its class that retains activity against viruses with reduced susceptibility to protease inhibitors.

Principles of Infectious Diseases and Epidemiology

Enfuvirtide targets a gp41 region of the viral envelope and stops the fusion process before the cell is infected. This drug needs to be injected twice daily and its use is reserved for treatment of heavily drug-experienced patients since it can help overcome existing drug resistance. Compounds that have been designed to inhibit resistant viruses are urgently needed since many patients treated during the past decades harbour viral strains with reduced susceptibilities to many if not all available drugs table 3.

Drugs belong to five drug classes and target three dir erent viral steps entry, reverse transcription, or protease. Availability of these drugs in resource-limited countries is subject to country specific licensing agreements. The goal of antiretroviral treatment is to decrease the morbidity and mortality that is generally associated with HIV-1 infection.

A combination of three or more active drugs is needed to achieve this aim in most patients. High rate of viral replication, low fidelity of reverse transcription, and the ability to recombine are the viral characteristics that lead to the diversity of HIV-1 species quasi-species in chronically infected individuals. This high genetic variability provided the rationale for highly active antiretroviral treatments HAART.

By combination of several potent antiretroviral agents, viral replication is suppressed to such low levels that emergence of drug resistant HIV-1 variants was, if not prevented, at least delayed. Widespread introduction of HAART in industrialised countries resulted in a striking decrease in morbidity and mortality, putting forward the hope that HIV-1 infection can be transformed into a treatable chronic disease. The wide application of this principle is restricted by long-term drug toxicities that lead to reduction of quality of life, and by treatment costs.

Toxicities eg, renal, hepato, mitochondrial , metabolic changes eg, lipodystrophy, diabetes mellitus , and immune reconstitution disease are some of the long-term problems that complicate decade-long HAART. One strategy addressing life-long daily compliance to HAART has been structured treatment interruptions. If successful, this strategy could limit drug toxicity and reduce treatment costs.

The transformation of AIDS into a chronic disease in industrialised countries has yet to be realised in resource-constrained settings. Access to HAART is an absolute humanitarian necessity to avert mortality in people who are central to the future survival of their countries. Emergence of drug resistance is the most common reason for treatment failure. Insufficient compliance, drug side-effects, or drug-drug interactions can lead to suboptimum drug concentrations, resulting in viral rebound.

Viral resistance has been described to every antiretroviral drug and therefore poses a serious clinical as well as public-health problem. Short-term antiretroviral-based interventions are effective in prevention of mother-to-child transmission. However, these interventions could result in drug resistant viral variants in the mother, baby, or both. Viral reservoirs consist of anatomical sanctuaries and a small pool of infected long-lived memory T lymphocytes.

HIV-1 latency in long-lived cell populations eg, memory T lymphocytes, macrophages poses an obstacle to eradication because current antiviral combination treatments fail to eliminate integrated proviruses from resting cells. Different strategies, including immune-modulatory molecules interleukin 2, anti-CD3 mAb, interleukin 7 , have been used to reactivate resting cells in the setting of HAART. Histone deacetylase-1 inhibitors, like valproic acid, release an inherent transcriptional block and by doing so facilitate viral long terminal repeat-driven expression.

Prevention of mother-to-child transmission has seen advances in both industrialised and resource-constrained settings. Because HIV-1 can be transmitted by breastfeeding, replacement feeding is recommended in many settings. Poor access to clean running water precludes, however, the use of formula feeding under these circumstances, and exclusive breastfeeding with abrupt weaning is one option for reducing transmission. Reduction of heterosexual transmission is crucial for control of the epidemic in many parts of the world.

The first can be achieved through abstinence and sex between concordantly seronegative individuals. Abstinence and lifelong monogamous relationships might not be adequate solutions for many people and therefore several interventions aimed at lowering the risk of transmission per discordant sexual act are in the process of clinical testing. Male and female condoms provide a proven and affordable prevention option. Other biomedical prevention interventions include male circumcision, antiretrovirals for prevention eg, pre-exposure or post-exposure , chemoprophylactic treatment of herpes simplex virus-2 HSV-2 , microbicides, and vaccines.

Results from one of three independent phase III male circumcision trials underway in South Africa, Kenya, and Uganda has helped to allay some of the ambivalence around the protective effect of male circumcision. Immunofluorescence studies of foreskin mucosa suggest that these tissues might be more susceptible to HIV-1 infection than cervical mucosa. Since high plasma viraemia increases the risk of transmission by as much as an order of magnitude, 21 does reducing viral load in the infected partner through, for example, antiretroviral treatment reduce the risk of HIV-1 transmission in the uninfected sexual partner?

Concerns were centred on clinical trials in resource-poor settings and the perceived scarcity of adequate interventions protecting these vulnerable populations. For example, there seems to be a correlation between levels of sexual hormones eg, progesterone and transmission risk. Periodic presumptive treatment for vaginal infections is being explored as an HIV-1 prevention strategy. Although the three phase III trial results of the first microbicidal product nonoxynol-9 done in the mids and s did not show protective effects, , they have informed the medical knowledge in terms of product selection, clinical testing, and safety assessments.

The past 5 years have seen major advances in investment and product development. The development of antiretroviral gels increased the specificity of these third generation microbicides in relation to surfactants, vaginal enhancers, or entry inhibitors that have dominated the product pipeline so far figure 5. The first antiretroviral gel to undergo early testing is tenofovir gel, and the findings in terms of safety profile, tolerance, low systemic absorption, and slight adverse events are promising.

Additional challenges are adherence to product use and the high rates of pregnancy in trial participants. A safe, protective, and inexpensive vaccine would be the most efficient and possibly the only way to curb the HIV pandemic. Safety concerns prohibit the use of live-attenuated virus as immunogen. Overcoming pre-existing immunity against replication incompetent immunogenic vectors eg, recombinant adenovirus type 5 is one of the challenges.

An important gateway to both prevention and care is knowledge of HIV-1 status. These changes will result in a shift in prevention efforts from a focus on individuals not infected with HIV-1 to a more effective continuum of prevention that includes uninfected, recently infected, infected, and asymptomatic people, as well as those with advancing HIV disease and on antiretroviral therapy. Much progress has been made in a short space of time, despite many scientific and programmatic challenges figure 6.

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In the absence of a protective vaccine or a cure, prevention and access to antiretroviral treatments are the best options to slow down the HIV-1 pandemic. Broad implementation of these principles needs improved infrastructures in resource-constrained regions, which have been and will continue to be most affected. The fact that HIV-1 is predominantly sexually transmitted and disproportionately affects populations that are already socially or economically marginalised, or both, poses many ethical, social, economic, and political challenges.

Estimates place the cross species transmission events leading to the worldwide spread of HIV-1 to the early decades of the 20th century. Numbers circled by a hexagon identify the specific year of an event. In view of the immediacy of the problem, and the fact that both research and programmes are mainly funded by the public sector, there is a greater demand from civil society for co-ownership of research and accountability for use of public funds. On the one hand, this co-ownership defines a changing role and responsibility of science in society, and on the other hand, shows a necessary synergy between activism and science.

This partnership has been invaluable for antiretroviral drug development, treatment access in resource-constrained settings, and the scale-up of interventions to reduce mother-to-child transmission. The increasing number of infected women and the disproportionate burden of infection in resource-constrained settings creates a scientific imperative to ensure research is done for people and in settings who stand to benefit most.

The most affected countries face many other economic, political, and development challenges, which have raised issues in undertaking multicentre and multicountry research. Research addressing women-specific topics such as effect of sexual hormones on transmission and disease progression, viral diversity, and antiretroviral potency and women-specific prevention interventions including microbicides is crucial.

We are probably at one of the most hopeful and optimistic points in our response to the pandemic. There is definitely more attention being directed to HIV-1, more resources panel , more civil society mobilisation, more governments speaking up, more possibilities for treatment, and more evidence about what prevention and treatment strategies will work than in previous years. The unrelenting growth of the pandemic tells us that current strategies are not enough.

Clearly, we need to do some things differently, while also increasing the scale and magnitude of current strategies in keeping with the pandemic.

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A comprehensive literature review was undertaken by searching the PubMed database online, for English language publications between January, , and June, Various combinations of these words were entered. All duplicate articles were removed. A subset of relevant articles was chosen and full-text manuscripts were summarised.

M Boettiger and C Baxter assisted with literature searches. Conflict of interest statement. Products or work from these companies are not discussed in the review. He holds patents on vaccine candidates. The other authors declare no conflict of interest. Europe PMC requires Javascript to function effectively. Recent Activity. This transformation has yet to be realised in those parts of the world that continue to bear a disproportionate burden of new HIV-1 infections and are most affected by increasing morbidity and mortality.

The snippet could not be located in the article text. This may be because the snippet appears in a figure legend, contains special characters or spans different sections of the article. Author manuscript; available in PMC Aug 2. PMID: Copyright notice. The publisher's final edited version of this article is available at Lancet.

See commentary " Non-sterile injections, contaminated blood, and the spread of HIV. See other articles in PMC that cite the published article. Abstract The HIV-1 pandemic is a complex mix of diverse epidemics within and between countries and regions of the world, and is undoubtedly the defining public-health crisis of our time. Open in a separate window. Figure 1. Figure 2. Pathogenesis of HIV-1 The worldwide spread of HIV-1 indicates that the virus effectively counteracts innate, adapted, and intrinsic immunity.

Figure 3. Figure 4. Table 1 Some of the host factors affecting susceptibility to HIV-1 infection. Clinical management Diagnosis The diagnosis of HIV-1 infection is based on the detection of specific antibodies, antigens, or both, and many commercial kits are available. Drug treatment Antiretroviral compounds Antiretroviral treatment is the best option for longlasting viral suppression and, subsequently, for reduction of morbidity and mortality. Combination antiretroviral treatment High rate of viral replication, low fidelity of reverse transcription, and the ability to recombine are the viral characteristics that lead to the diversity of HIV-1 species quasi-species in chronically infected individuals.

HAART in resource-constrained settings The transformation of AIDS into a chronic disease in industrialised countries has yet to be realised in resource-constrained settings. Drug resistance Emergence of drug resistance is the most common reason for treatment failure. Viral reservoirs Viral reservoirs consist of anatomical sanctuaries and a small pool of infected long-lived memory T lymphocytes. Prevention Mother-to-child transmission Prevention of mother-to-child transmission has seen advances in both industrialised and resource-constrained settings.

Sexual transmission Reduction of heterosexual transmission is crucial for control of the epidemic in many parts of the world. Figure 5. Table 4 Summary of microbicides currently undergoing advanced clinical testing. Vaccines A safe, protective, and inexpensive vaccine would be the most efficient and possibly the only way to curb the HIV pandemic. Conclusions An important gateway to both prevention and care is knowledge of HIV-1 status.

Figure 6. Search strategy and selection criteria A comprehensive literature review was undertaken by searching the PubMed database online, for English language publications between January, , and June, References 1. AIDS Care. Hayes R, Weiss H. Understanding HIV epidemic trends in Africa.

Quinn TC, Overbaugh J. Int J Epidemiol. Shisana O, Davids A. Bull World Health Organ. Male circumcision for prevention of heterosexual acquisition of HIV in men. Cochrane Database Syst Rev. Advances in multilevel approaches to understanding the epidemiology and prevention of sexually transmitted infections and HIV: an overview. J Infect Dis. A systematic review of the epidemiologic interactions between classic sexually transmitted diseases and HIV: how much really is known? Sex Transm Dis. Determinants of the impact of sexually transmitted infection treatment on prevention of HIV infection: a synthesis of evidence from the Mwanza, Rakai, and Masaka intervention trials.

Community effects on the risk of HIV infection in rural Tanzania. Sex Transm Infect.