Elimination Of Human Immunodeficiency Virus Research Articles

Can the Heterosexual HIV Epidemic be Eliminated in South Africa Using Combination Prevention? A Modeling Analysis.

Little is known about how combining efficacious interventions for human immunodeficiency virus (HIV) prevention could lead to HIV elimination. We used an agent-based simulation model, the HIV calibrated dynamic model, to assess the potential for HIV elimination in South Africa. We examined several scenarios (from continuation of the current status quo to perfect achievement of targets) with differing combinations of male condom use, adult male circumcision, HIV testing, and early antiretroviral therapy (ART). We varied numerous parameters, including the proportion of adult males circumcised, the frequency of condom use during sex acts, acceptance of HIV testing, linkage to health care, criteria for ART initiation, ART viral suppression rates, and loss to follow-up. Maintaining current levels of combination prevention would lead to increasing HIV incidence and prevalence in South Africa, while the perfect combination scenario was projected to eliminate HIV on a 50-year time scale from 2013 to 2063. Perfecting testing and treatment, without changing condom use or circumcision rates, resulted in an 89% reduction in HIV incidence but not elimination. Universal adult male circumcision alone resulted in a 21% incidence reduction within 20 years. Substantial decreases in HIV incidence are possible from sufficient uptake of both primary prevention and ART, but with continuation of the status quo, HIV elimination in South Africa is unlikely within a 50-year time scale.

Strategies to increase the activity of microglia as efficient protectors of the brain against infections.

In healthy individuals, infections of the central nervous system (CNS) are comparatively rare. Based on the ability of microglial cells to phagocytose and kill pathogens and on clinical findings in immunocompromised patients with CNS infections, we hypothesize that an intact microglial function is crucial to protect the brain from infections. Phagocytosis of pathogens by microglial cells can be stimulated by agonists of receptors of the innate immune system. Enhancing this pathway to increase the resistance of the brain to infections entails the risk of inducing collateral damage to the nervous tissue. The diversity of microglial cells opens avenue to selectively stimulate sub-populations responsible for the defence against pathogens without stimulating sub-populations which are responsible for collateral damage to the nervous tissue. Palmitoylethanolamide (PEA), an endogenous lipid, increased phagocytosis of bacteria by microglial cells in vitro without a measurable proinflammatory effect. It was tested clinically apparently without severe side effects. Glatiramer acetate increased phagocytosis of latex beads by microglia and monocytes, and dimethyl fumarate enhanced elimination of human immunodeficiency virus from infected macrophages without inducing a release of proinflammatory compounds. Therefore, the discovery of compounds which stimulate the elimination of pathogens without collateral damage of neuronal structures appears an achievable goal. PEA and, with limitations, glatiramer acetate and dimethyl fumarate appear promising candidates.

Seminal Human Immunodeficiency Virus Blips and Structured Natural Conception In Serodiscordant Couples

TO THE EDITOR—As the prognosis for human immunodeficiency virus (HIV)– infected patients has improved with effective therapies, the prospect of raising children has become a realistic expectation among many serodiscordant couples. For seronegative women, structured natural conception can offer an appealing (and affordable) balance between getting pregnant and avoiding infection from their seropositive male partner. However, despite sustained long-term suppression of plasma viremia by antiretroviral therapy below the level of detection, some HIV-infected men intermittently and unpredictably have detectable free or cell-associated HIV in their semen, independent of drug regimen or seminal drug levels [1–4]. Shedding has been associated with transient increases in T-cell activation confined to the male genital tract [4–6]. The finite (albeit quite small) possibility of infecting a seronegative partner during intercourse even when the seropositive patient has plasma virus fully suppressed looms over structured natural conception initiatives for discordant heterosexual couples wanting offspring [1, 7, 8]. Unfortunately, an absolute zero risk for a coital act seems theoretically unattainable, given the limitations of current interventions, since elimination of cellassociated HIV is not yet achievable [9]. Integrated proviral DNA lies dormant in compartmentalized cellular reservoirs, prominently including the neurological and genitourinary compartments. When HIV-harboring cells within a compartment are stimulated, site-specific viral blips occur irrespective of systemic events in blood and elsewhere. Restricted by their specific mechanism of action, drugs targeting isolated intracellular steps in the preintegration viral life cycle cannot interfere with release of virus during the first ensuing cycle after activation [10]. Even when pregnancy is the goal, unprotected intercourse should be avoided in the presence of recognized sexually transmitted diseases or other genitourinary infections; however, self-limited productive HIV infection is likely more often triggered by subclinical and, thus, unsuspected inflammation (such as asymptomatic shedding of herpesviruses) [5, 6, 11, 12]. The very small residual risk of HIV transmission associated with structured natural conception may be acceptable to qualifying and well-informed couples (especially when other options are unavailable or impractical), but the ultimate decision maker must always be the unharassed female partner [13–15].

Fifteen million people on antiretroviral treatment by 2015

The declaration of the United Nations High Level meeting on AIDS in June 2011 includes 10 concrete targets, including to ensure that there are 15 million people living with human immunodeficiency virus (HIV) on antiretroviral treatment (ART) by 2015. This review examines the potential, opportunities and challenges of treatment as prevention of HIV and tuberculosis (TB) in reaching this target. Although around 8 million people are on treatment, everyone living with HIV will eventually need ART to stay alive. As many as 24 million people living with HIV today are not on treatment, the majority not even being aware of their HIV infection. Expansion of a comprehensive prevention strategy including providing ART to 15 million or more people would significantly reduce HIV and TB morbidity, mortality and transmission. The challenges include ensuring human rights protections, steady drug supply, early diagnosis and linkage to care, task shifting, adherence, retention, and monitoring and evaluation. Expansion could also lead to the control and possible elimination of HIV in many places. Achieving an 'AIDS-free generation' whereby deaths related to HIV are drastically reduced, people living with HIV are AIDS-free on ART, and HIV transmission is decreased, is both scientifically sound and practically feasible. The global community could reach 15 million people on ART by 2015 while expanding our vision and efforts to include diagnosis and treatment for all the 32 million people living with HIV in the future.

Elimination of paediatric HIV in KwaZulu-Natal, South Africa: large-scale assessment of interventions for the prevention of mother-to-child transmission

To report the rates of mother-to-child transmission (MTCT) of the human immunodeficiency virus (HIV), and the coverage of interventions designed to prevent such transmission, in KwaZulu-Natal. Mothers with infants aged ≤ 16 weeks and fathers or legal guardians with infants aged 4-8 weeks who, between May 2008 and April 2009, attended immunization clinics in six districts of KwaZulu-Natal were included. The mothers' uptake of interventions for the prevention of MTCT was explored. Blood samples from infants aged 4-8 weeks were tested for anti-HIV antibodies and, if antibody-positive, for HIV desoxyribonucleic acid (DNA). Of the 19,494 mothers investigated, 89·9% reported having had an HIV test in their recent pregnancy. Of the 19,138 mothers who reported ever having had an HIV test, 34.4% reported that they had been found HIV-positive and, of these, 13.7% had started lifelong antiretroviral treatment and 67.2% had received zidovudine and nevirapine. Overall, 40.4% of the 7981 infants tested were found positive for anti-HIV antibodies, indicating HIV exposure. Just 7.1% of the infants checked for HIV DNA (equating to 2.8% of the infants tested for anti-HIV antibodies) were found positive. The low levels of MTCT observed among the infants indicate the rapid, successful implementation of interventions for the prevention of such transmission. Sampling at immunization clinics appears to offer a robust method of estimating the impact of interventions designed to reduce such transmission. Large-scale elimination of paediatric HIV infections appears feasible, although this goal has not yet been fully achieved in KwaZulu-Natal.

Towards a world free from HIV and AIDS?

Approximately 30 years ago, in June 1981, it was reported from theCenter forDiseaseControl andPrevention (CDC) that five, otherwise healthy, homosexual men in California had presented with pneumonia caused by Pneumocystis jiroveci pneumonia, a rare disease seen exclusively in individualswith a severely suppressed immune system. Several reports confirmed the initial observation and lent support to the possibility that a new sexually transmitted, infectious agent was circulating within the gay community in the United States. The clinical condition was named acquired immunodeficiency syndrome (AIDS). Two years later, a research team at the Institut Pasteur under the guidance of Francoise Barre-Sinoussi and Luc Montagnier isolated human immunodeficiency virus (HIV), the causative agent of AIDS, from a lymph node biopsy of a French patient. The isolation and characterization of HIV paved the way for the design of diagnosticmethods to identify the virus in blood andbloodproducts and towards the development of novel antiretroviral treatment (ART) to control HIV replication in infected patients. For their discoveries, Barre-Sinoussi and Montagnier were awarded the Nobel Prize in Physiology and Medicine in 2008.

Hide and Seek… Can We Eradicate HIV by Treatment Intensification?

Although the introduction of combination antiretroviral therapy (ART) in the mid-1990s led to a remarkable reduction of human immunodeficiency virus (HIV)–associated morbidity and mortality, eradication of the virus is still regarded as the holy grail by the HIV community. However, complete elimination of HIV has remained an elusive goal. Even patients who are successfully treated with ART for several years often do not achieve full recovery of their CD4 cell count (.500 cells/lL) and exhibit increased levels of immune activation along with its detrimental effects [1]. In addition, low levels of viremia can be readily detected by sensitive single copy assays [2]. The underlying reasons for the persistent immune activation detected in these patients are not entirely understood. Although the role of microbial translocation stemming from a ‘‘leaky gut’’ in the HIV-infected patient has become more evident [3], immune activation may at least partially be caused by ongoing low-level viral replication. Residual viremia may stem from ongoing cycles of viral replication and infection of new cells, for which additional intensification of ART might be useful. Alternatively, viremia might stem from the release of virions from stable reservoirs of latently infected cells. Because no full cycle of viral replication would be needed for HIV release, intensification would be potentially fruitless in this situation [4, 5]. Thus far, all approved antiretroviral drugs have worked through interference with active viral replication but have not targeted latent infection. The advent and approval of new drug classes with new modes of action, namely integrase inhibitors and CCR5 antagonists, have revived treatment strategies aimed at eradication of HIV infection. In the absence of a cure, these strategies may at least further reduce persistent viral load and/or decrease immune activation. In this issue of the Journal, Hatano et al [6] present the latest of a series of clinical studies published over the past year (Table 1) that have examined the consequence of treatment intensification with raltegravir, a new and potent antiretroviral HIV integrase inhibitor approved by the US Food and Drug Administration in 2007. Initial kinetic calculations predicted that treatment intensification could, indeed, have an effect on re-infection of latently infected cells and impact residual low-level viremia [11]. In an earlier treatment intensification trial, Buzon et al [7] randomized 69 patients to receive treatment intensification with raltegravir in addition to conventional highly active antiretroviral therapy (HAART; 45 patients in the raltegravir treatment intensification arm, and 24 patients in the control group). The authors used a novel approach to assess the presence of low-level persistent replication, namely quantification of long terminal repeat (LTR) circles. During HIV replication, a small proportion of the linear HIV complementary DNA (cDNA) is circularized by host DNA repair enzymes and circular episomes, with 1 or 2 copies of the LTRs (1-LTRs or 2-LTRs) produced. Because raltegravir blocks integration of viral linear cDNA into genomic host cell DNA, any residual viral replication should lead to an increase of the number of LTR circles [12, 13]. The authors of this study, indeed, measured a significant, albeit transient, increase of the 2-LTRs circles in up to 30% of patients in the raltegravir group, but in only 5% of the control group [7]. Of note, however, 2-LTR circles were detectable at baseline in 5 patients in the intensification group, but not in the control group. A post hoc analysis of the subgroup of patients in whom 2-LTR circles were detected revealed that 61% of these Received and accepted 23 November 2010. Potential conflicts of interest: J.v.L. and J.S.z.W. have received speaker honoraria from Essex Pharma. J.v.L. was a clinical trials investigator, received speaker honoraria, and was a member of an advisory board for Merck. Reprints or correspondence: Jan van Lunzen, PhD, MD, Dept of Medicine, Infectious Diseases Unit, University Medical Center Hamburg-Eppendorf, Martinistr, 52, 20246 Hamburg, Germany (v.lunzen@uke.uni-hamburg.de). The Journal of Infectious Diseases 2011;203:894–7 The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com 1537-6613/2011/2037-0001$15.00 DOI: 10.1093/infdis/jiq150

Modeling the effect of high dead‐space syringes on the human immunodeficiency virus (HIV) epidemic among injecting drug users

To illustrate the impact of different proportions of injecting drug users (IDUs) sharing high dead-space syringes (HDSS) or low dead-space syringes (LDSS) on the probability of human immunodeficiency virus (HIV) transmission; and thus the impact on injection-related HIV prevalence and incidence. A stochastic mathematical model was used to evaluate the impact of HDSS use in high- and low-risk IDU populations. Model parameters were obtained from peer-reviewed publications. Analytical solutions of a simplified deterministic model were obtained to explain the effect of HDSS on HIV endemic states. Simulation analysis shows that the HIV epidemic could be sustained even when a small percentage of sharing (10%) involved HDSS. The effect is much stronger in high-risk compared with low-risk populations. Steady state HIV prevalence increases with the proportion of HDSS, and for high- and low-risk populations reaches around 80% and 20%, respectively. For low-risk populations, the use of LDSS could result in the virtual elimination of HIV. These results are dependent upon an evidence-supported assumption of a significant difference in HIV transmission risk associated with HDSS versus LDSS. Our models suggest that injection-related HIV epidemics may not occur when most (e.g. 95% or more) IDUs use LDSS. While these results are based on indirect risk measures and a number of simplifying assumptions, the effect of blood retained in high dead-space syringes on HIV prevalence seems to be very strong, even using relatively conservative assumptions. The findings have potential implications for needle exchange programs and the types of syringes produced and distributed world-wide.

Elimination of HIV infection in infants in Europe—Challenges and demand for response

Effective interventions for the prevention of mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) infection now exist and where these are fully implemented, MTCT rates of 1-2% are achievable. Virtual elimination of HIV in infants by 2010 has therefore been set as a goal for European region. There are, however, many challenges. The eastern European and central Asian countries are facing the fastest growing HIV epidemic in the world with a dramatic increase in numbers of HIV-positive pregnancies and new HIV infected infants. Nevertheless, the prevalence of HIV among pregnant women is still relatively low and the high coverage with antenatal care provide an opportunity to decrease the number of new HIV cases among infants to minimal level. The challenge is to move national strategies for prevention of HIV infection among infants from a disease-focused vertical approach towards effective preventive interventions integrated into mother-child health (MCH) and reproductive health services. The scaling up of prevention interventions among those most at risk and hard-to-reach women are key priority actions. This goes beyond clinical care and needs to include a range of care and protection issues, both in health institutions and in the community. The WHO Regional Office for Europe, together with other UNAIDS co-sponsors, has developed a regional strategic framework for prevention of HIV infection in infants. The strategic framework promotes a comprehensive approach comprising the four interrelated elements: (1) primary prevention of HIV infection; (2) prevention of unintended pregnancies among HIV-infected women; (3) prevention of HIV transmission from HIV-infected women to their children; (4) provision of care and support to HIV-infected women, their infants and families. Implementation of all four pillars of the strategic framework would help European countries to achieve the goal of virtual elimination of HIV infection in infants.

Could a simple surgical intervention eliminate HIV infection?

BackgroundHuman Immunodeficiency Virus (HIV) infection is a dynamic interaction of the pathogen and the host uniquely defined by the preference of the pathogen for a major component of the immune defense of the host. Simple mathematical models of these interactions show that one of the possible outcomes is a chronic infection and much of the modelling work has focused on this state.BifurcationHowever, the models also predict the existence of a virus-free equilibrium. Which one of the equilibrium states the system selects depends on its parameters. One of these is the net extinction rate of the preferred HIV target, the CD4+ lymphocyte. The theory predicts, somewhat counterintuitively, that above a critical extinction rate, the host could eliminate the virus. The question then is how to increase the extinction rate of lymphocytes over a period of several weeks to several months without affecting other parameters of the system.Testing the hypothesisProposed here is the use of drainage, or filtration, of the thoracic duct lymph, a well-established surgical technique developed as an alternative for drug immunosuppression for organ transplantation. The performance of clinically tested thoracic duct lymphocyte depletion schemes matches theoretically predicted requirements for HIV elimination.

From the cell to the community: AIDS research in California

Between 1981 and 1999, more than 110,00 cases of the acquired immunodeficiency syndrome (AIDS) have been reported in California, of whom nearly 70,000 patients have died. Since 1983, the University of California has funded basic, clinical, social, and behavioral research on the human immunodeficiency virus (HIV)/AIDS through the University wide AIDS ResearchProgram (UARP). Major accomplishments of UARP-supported research include the isolation and characterization of HIV, the detection and elimination of HIV in blood clotting factor VIII, and in early studies, the demonstration of the rapid production and turnover of HIV in the blood of infected persons. Together with its advisory group, the University wide Task Force on AIDS, UARP convenes an annual meeting that provides an opportunity for the exchange of new information on HIV/AIDS in California. Participants include bench scientists, clinicians, policymakers, outreach workers, community-based organizations, and members of affected communities. Most of the studies presented at the UARP conference are in their early stages and modestly funded. While some go on to receive larger federal grants, others are quickly integrated into new interventions or investigations. In this issue of wjm, we share highlights of the 3rd AnnualConference on AIDS Research inCalifornia.† The plenarytheme for the year 2000 was “Early Events and Intervention in HIVInfection.” Although the recent and ongoing advances in highly active antiretroviral therapy are well known, the meeting provided a fertile venue for presenting other innovative areas for treatment and prevention.

Magnetoliposomes may be useful for elimination of HIV from infected individuals.

A simple method is proposed for the treatment of the acquired immunodeficiency syndrome (AIDS) by introducing into the blood stream magnetoliposomes with coupled human immunodeficiency virus (HIV) receptor proteins. After some time lag, needed for binding of HIV and HIV-infected cells to magnetoliposomes, the arterio-venous shunt, as used with dialysis patients should be inserted and the patient's blood should be passed through multiple tubes filled with stainless steel wool, each of which is surrounded by a coil producing a strong non-homogeneous magnetic field, which may result in a substantial reduction of HIV and HIV-infected cells in the infected body.

Foreign-protein-mediated immunodeficiency in hemophiliacs with and without HIV.

Hemophilia-AIDS has been interpreted in terms of two hypotheses: the foreign-protein-AIDS hypothesis and the Human Immunodeficiency Virus (HIV)-AIDS hypothesis. The foreign-protein-AIDS hypothesis holds that proteins contaminating commercial clotting factor VIII cause immunosuppression. The foreign-protein hypothesis, but not the HIV hypothesis, correctly predicts seven characteristics of hemophilia-AIDS: 1) The increased life span of American hemophiliacs in the two decades before 1987, although 75% became infected by HIV--because factor VIII treatment, begun in the 1960s, extended their lives and simultaneously disseminated harmless HIV. After 1987 the life span of hemophiliacs appears to have decreased again, probably because of widespread treatment with the cytotoxic anti-HIV drug AZT. 2) The distinctly low, 1.3-2%, annual AIDS risk of hemophiliacs, compared to the higher 5-6% annual risk of intravenous drug users and male homosexual aphrodisiac drug users--because transfusion of foreign proteins is less immunosuppressive than recreational drug use. 3) The age bias of hemophilia-AIDS, i.e. that the annual AIDS risk increased 2-fold for each 10-year increase in age--because immunosuppression is a function of the lifetime dose of foreign proteins received from transfusions. 4) The restriction of hemophilia-AIDS to immunodeficiency diseases--because foreign proteins cannot cause non-immunodeficiency AIDS diseases, like Kaposi's sarcoma. 5) The absence of AIDS diseases above their normal background in sexual partners of hemophiliacs--because transfusion-mediated immunotoxicity is not contagious. 6) The occurrence of immunodeficiency in HIV-free hemophiliacs--because foreign proteins, not HIV, suppress their immune system. 7) Stabilization, even regeneration, of immunity of HIV-positive hemophiliacs by long-term treatment with pure factor VIII. This shows that neither HIV nor factor VIII plus HIV are immunosuppressive by themselves. Therefore, AIDS cannot be prevented by elimination of HIV from the blood supply and cannot be rationally treated with genotoxic antiviral drugs, like AZT. Instead, hemophilia-AIDS can be prevented and has even been reverted by treatment with pure factor VIII.

Recombinant CD4‐IgE, a novel hybrid molecule, inducing basophils to respond to human immunodeficiency virus (HIV) and HIV‐infected target cells

Basophils and mast cells, as the main effector cells in IgE-mediated type I hypersensitivity, are involved in the elimination of parasites and, according to recent findings, may also play an important role in the defense against bacterial and viral infections. Using a genetic engineering approach we wanted to redirect this potent IgE-mediated defense system against intruding human immune deficiency virus. We constructed a recombinant CD4-IgE molecule, consisting of the two N-terminal domains of CD4 and the CH2-4 domains of the IgE heavy chain, thus providing the IgE with specificity for the gp120 of human immunodeficiency virus (HIV). The binding properties of hybrid CD4-IgE to the high-affinity receptor for IgE (Fc epsilon RI) on basophils as well as to the low-affinity receptor (Fc epsilon RII or CD23) for IgE on lymphoid cells were found to be similar to those of native IgE. At the same time, the CD4 domains of the recombinant molecule retained the gp120 binding specificity with an affinity similar to that of the native CD4. By functional tests, we demonstrated that CD4-IgE armed basophils can be triggered by free HIV and by HIV-infected cells to release their mediators. We further show that HIV-triggered basophils lead to a decreased replication of HIV in susceptible T cells. We, therefore, conclude that the type I hypersensitivity effector cells can be engaged in the elimination of HIV-infected cells, at least in vitro. Because of the strong binding of the CD4-IgE construct to the Fc epsilon RI, we assume that CD4-IgE has a short t1/2 in serum, but may similarly to IgE exhibit prolonged resident time on basophils and mast cells, which are located close to mucosal surfaces or in the connective tissue. Thus CD4-IgE could play an important role in the elimination of HIV also in vivo.

Elimination of high titre HIV from fibreoptic endoscopes.

Concern about contamination of fibreoptic endoscopes with human immunodeficiency virus (HIV) has generated a variety of disruptive and possibly unnecessary infection control practices in endoscopy units. Current recommendations on the cleaning and disinfection of endoscopes have been formulated without applied experimental evidence of the effective removal of HIV from endoscopes. To study the kinetics of elimination of HIV from endoscope surfaces, we artificially contaminated the suction-biopsy channels of five Olympus GIF XQ20 endoscopes with high titre HIV in serum. The air and water channels of two instruments were similarly contaminated. Contamination was measured by irrigating channels with viral culture medium and collecting 3 ml at the distal end for antigen immunoassay. Endoscopes were then cleaned manually in neutral detergent according to the manufacturer's recommendations and disinfected in 2% alkaline glutaraldehyde (Cidex, Surgikos) for two, four, and ten minutes. Contamination with HIV antigens was measured before and after cleaning and after each period of disinfection. Initial contamination comprised 4.8 x 10(4) to 3.5 x 10(6) pg HIV antigen/ml. Cleaning in detergent achieved a reduction to 165 pg/ml (99.93%) on one endoscope and to undetectable levels (100%) on four. After two minutes in alkaline glutaraldehyde all samples were negative and remained negative after the longer disinfection times. Air and water channels, where contaminated, were tested after 10 minutes' disinfection and were negative. These findings underline the importance of cleaning in removing HIV from endoscope and indicate that the use of dedicated equipment and long disinfection times are unnecessary.