Biomarker reveals HIV's hidden reservoir.

Determining the total amount of HIV DNA in people undergoing antiretroviral therapy could accelerate the development of novel therapies and potential cures for HIV infection

Transmitted Minority Drug-Resistant HIV Variants: A New Epidemic?

Steven Deeks discusses a new study that investigates the prevalence and clinical implications of transmitted minority drug-resistant HIV variants

The end of HIV: Still a very long way to go, but progress continues.

In an Editorial accompanying PLOS Medicine's Special Issue on Advances in Prevention, Treatment and Cure of HIV/AIDS, Guest Editors Steven Deeks, Sharon Lewin, and Linda-Gail Bekker discuss priorities in the field and the content of the issue

Maximising the global health impact of future HIV cure-related interventions through advance planning

Thinking about public health impact should inform HIV curative investigations. Should an effective HIV cure or sustained viral remission intervention emerge from ongoing investigations, implementation strategies aimed at ensuring global access will be needed if these approaches are to be impactful, and planning accordingly makes sense now. Specifically, we discuss three key access barriers to future cure-related interventions: high cost of the strategy; non-financial challenges to procurement, distribution and point-of-care delivery; and non-adherence and the need for long-term monitoring. As we argue, plans and decision-making for overcoming each of these barriers will need to be developed in advance. An evaluation of remaining barriers and likely global impact of the leading strategies under investigation should inform decisions on which strategy might receive funding priority. Among the strategies being investigated, implementation barriers for latency-reversing agents, immunotherapy and combination antiretroviral therapy (ART) may be overcome on a global scale with some effort. Overcoming implementation barriers for medically complex and high-risk interventions, such as stem cell and, to some degree, gene therapy, may be less feasible

Persistent HIV-1 replication during antiretroviral therapy

Altres ajuts: We appreciate the help of M.C. Puertas with graphics. Work in JMP group is supported by the Spanish Secretariat of Research (grant SAF2013-49042-R), the Spanish AIDS network 'Red Temática Cooperativa de Investigación en SIDA'(RD12/0017), the American Foundation for AIDS Research (amfAR), the FP7-HEALTH-2013-INNOVATION-1 through the iHIVARNA project, and the Agence Nationale de recherches sur la SIDA et les he'patites virales (ANRS).The present review will highlight some of the recent findings regarding the capacity of HIV-1 to replicate during antiretroviral therapy (ART). Although ART is highly effective at inhibiting HIV replication, it is not curative. Several mechanisms contribute to HIV persistence during ART, including HIV latency, immune dysfunction, and perhaps persistent low-level spread of the virus to uninfected cells (replication). The success in curing HIV will depend on efficiently targeting these three aspects. The degree to which HIV replicates during ART remains controversial. Most studies have failed to find any evidence of HIV evolution in blood, even with samples collected over many years, although a recent very intensive study of three individuals suggested that the virus population does shift, at least during the first few months of therapy. Stronger but still not definitive evidence for replication comes from a series of studies in which standard regimens were intensified with an integration inhibitor, resulting in changes in episomal DNA (blood) and cell-associated RNA (tissue). Limited drug penetration within tissues and the presence of immune sanctuaries have been argued as potential mechanisms allowing HIV to spread during ART. Mathematical models suggest that HIV replication and evolution is possible even without the selection of fully drug-resistant variants. As persistent HIV replication could have clinical consequences and might limit the efficacy of curative interventions, determining if HIV replicates during ART and why, should remain a key focus of the HIV research community. Residual viral replication likely persists in lymphoid tissues, at least in a subset of individuals. Abnormal levels of immune activation might contribute to sustain virus replication

Human endogenous retrovirus K106 (HERV-K106) was infectious after the emergence of anatomically modern humans.

HERV-K113 and HERV-K115 have been considered to be among the youngest HERVs because they are the only known full-length proviruses that are insertionally polymorphic and maintain the open reading frames of their coding genes. However, recent data suggest that HERV-K113 is at least 800,000 years old, and HERV-K115 even older. A systematic study of HERV-K HML2 members to identify HERVs that may have infected the human genome in the more recent evolutionary past is lacking. Therefore, we sought to determine how recently HERVs were exogenous and infectious by examining sequence variation in the long terminal repeat (LTR) regions of all full-length HERV-K loci. We used the traditional method of inter-LTR comparison to analyze all full length HERV-Ks and determined that two insertions, HERV-K106 and HERV-K116 have no differences between their 5' and 3' LTR sequences, suggesting that these insertions were endogenized in the recent evolutionary past. Among these insertions with no sequence differences between their LTR regions, HERV-K106 had the most intact viral sequence structure. Coalescent analysis of HERV-K106 3' LTR sequences representing 51 ethnically diverse individuals suggests that HERV-K106 integrated into the human germ line approximately 150,000 years ago, after the emergence of anatomically modern humans

Cerebrospinal fluid signs of neuronal damage after antiretroviral treatment interruption in HIV-1 infection

BACKGROUND: The neurofilament is a major structural component of myelinated axons. Increased cerebrospinal fluid (CSF) concentrations of the light chain of the neurofilament protein (NFL) can serve as a sensitive indicator of central nervous system (CNS) injury. To assess whether interrupting antiretroviral treatment of HIV infection might have a deleterious effect on the CNS, we measured NFL levels in HIV-infected subjects interrupting therapy. We identified subjects who had CSF HIV RNA concentrations below 50 copies/mL at the time combination antiretroviral therapy was interrupted, and for whom CSF samples were available before and after the interruption. RESULTS: A total of 8 subjects were studied. The median (range) CSF NFL level at baseline was <125 (<125–220) ng/L (normal <250 ng/L). All 8 subjects exhibited an increase in CSF and plasma HIV RNA after stopping therapy, accompanied by intrathecal immunoactivation as evidenced by CSF lymphocytic pleocytosis (7/8 patients) and increased CSF neopterin concentration (5/6 patients). Three subjects showed a consistent increase in CSF NFL, rising from <125 ng/L to a maximum of 880 (at day 148), 1,010 (day 58) and 10,930 ng/L (day 101). None exhibited new neurological symptoms or signs, or experienced functional deterioration during the period off treatment; of 5 who underwent brief quantitative neurological testing, none showed worsening performance. CONCLUSION: These findings suggest that resurgence of active HIV replication may result in measurable, albeit subclinical, CNS injury. Further studies are needed to define the frequency and pathobiological importance of the increase in CSF NFL

Mitral Annular and Coronary Artery Calcification Are Associated with Mortality in HIV-Infected Individuals.

BackgroundHIV infection increases cardiovascular risk. Coronary artery calcification (CAC) and mitral annular calcification (MAC) identify patients at risk for cardiovascular disease (CVD). The purpose of this study was to examine the association between MAC, CAC and mortality in HIV-infected individuals.Methods and resultsWe studied 152 asymptomatic HIV-infected individuals with transthoracic echocardiography (TTE) and computed tomography (CT). MAC was identified on TTE using standardized criteria. Presence of CAC, CAC score and CAC percentiles were determined using the modified Agatston criteria. Mortality data was obtained from the Social Security and National Death Indices (SSDI/NDI). The median age was 49 years; 87% were male. The median duration of HIV was 16 years; 84% took antiretroviral therapy; 64% had an undetectable viral load. CVD risk factors included hypertension (35%), smoking (62%) and dyslipidemia (35%). Twenty-five percent of individuals had MAC, and 42% had CAC. Over a median follow-up of 8 years, 11 subjects died. Subjects with CAC had significantly higher mortality compared to those with MAC only or no MAC. The Harrell's C-statistic of CAC was 0.66 and increased to 0.75 when MAC was added (p = 0.05). MAC, prior CVD, age and HIV viral load were independently associated with higher age- and gender-adjusted CAC percentiles in an adjusted model (p &lt; 0.05 for all).ConclusionIn HIV patients, the presence of MAC, traditional risk factors and HIV viral load were independently associated with CAC. Presence of CAC and MAC may be useful in identifying HIV-infected individuals at higher risk for death