Treatment to Prevent Transmission of HIV‐1

Antiretroviral agents (ART) have the potential to prevent HIV transmission by reducing the concentration of HIV in blood and genital secretions. Indeed, mathematical models with favorable assumptions suggest the potential of ART to stop the spread of HIV. Empirical results from ecological and population based studies, and several short term observational studies involving HIV discordant heterosexual couples suggest that ART reduces HIV transmission. A multinational randomized controlled trial (NIH NPTN052) also examining the reliability and durability of ART as prevention in HIV discordant couples is underway. The latter and other studies also consider sexual risk taking behavior, and transmission of HIV resistant variants when ART is used as prevention. Early HIV detection and treatment (“test and treat”) are being considered as an important prevention strategy. In this article, we review the data supporting the use of ART to prevent HIV transmission, and critically examine the public health implications of this strategy

Vorinostat Renders the Replication-Competent Latent Reservoir of Human Immunodeficiency Virus (HIV) Vulnerable to Clearance by CD8 T Cells

Latently human immunodeficiency virus (HIV)-infected cells are transcriptionally quiescent and invisible to clearance by the immune system. To demonstrate that the latency reversing agent vorinostat (VOR) induces a window of vulnerability in the latent HIV reservoir, defined as the triggering of viral antigen production sufficient in quantity and duration to allow for recognition and clearance of persisting infection, we developed a latency clearance assay (LCA). The LCA is a quantitative viral outgrowth assay (QVOA) that includes the addition of immune effectors capable of clearing cells expressing viral antigen. Here we show a reduction in the recovery of replication-competent virus from VOR exposed resting CD4 T cells following addition of immune effectors for a discrete period. TAKE HOME MESSAGE: VOR exposure leads to sufficient production of viral protein on the cell surface, creating a window of vulnerability within this latent reservoir in antiretroviral therapy (ART)-suppressed HIV-infected individuals that allows the clearance of latently infected cells by an array of effector mechanisms

Interval dosing with the HDAC inhibitor vorinostat effectively reverses HIV latency

BACKGROUND. The histone deacetylase (HDAC) inhibitor vorinostat (VOR) can increase HIV RNA expression in vivo within resting CD4+ T cells of aviremic HIV+ individuals. However, while studies of VOR or other HDAC inhibitors have reported reversal of latency, none has demonstrated clearance of latent infection. We sought to identify the optimal dosing of VOR for effective serial reversal of HIV latency

Acute HIV infection among pregnant women in Malawi

There are limited data on acute HIV infection (AHI) prevalence during pregnancy

Patterns of periodontal disease progression based on linear mixed models of clinical attachment loss

AimThe goal of the present longitudinal cohort study was to examine patterns of periodontal disease progression at progressing sites and subjects defined based on linear mixed models (LMM) of clinical attachment loss (CAL).Materials and MethodsA total of 113 periodontally healthy and 302 periodontitis subjects had their CAL calculated bimonthly for 12 months. LMMs were fitted for each site and the predicted CAL levels used to categorize their progression state. Participants were grouped based on the number of progressing sites into unchanged, transitional and active subjects. Patterns of periodontal disease progression were explored using descriptive statistics.ResultsProgression occurred primarily at molars (50% of progressing sites) and inter‐proximal sites (72%), affected a higher proportion of deep than shallow sites (2.7% versus 0.7%), and pocketing was the main mode of progression (49%). We found a low level of agreement (47%) between the LMM and traditional approaches to determine progression such as change in CAL ≥3 mm. Fourteen per cent of subjects were classified as active and among those 93% had periodontitis. The annual mean rate of progression for the active subjects was 0.35 mm/year.ConclusionProgressing sites and subjects defined based on LMMs presented patterns of disease progression similar to those previously reported in the literature.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142020/1/jcpe12827.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142020/2/jcpe12827_am.pd

Screening Yield of HIV Antigen/Antibody Combination and Pooled HIV RNA Testing for Acute HIV Infection in a High-Prevalence Population

Although acute HIV infection contributes disproportionately to onward HIV transmission, HIV testing has not routinely included screening for acute HIV infection. To evaluate the performance of an HIV antigen/antibody (Ag/Ab) combination assay to detect acute HIV infection compared with pooled HIV RNA testing. Multisite, prospective, within-individual comparison study conducted between September 2011 and October 2013 in 7 sexually transmitted infection clinics and 5 community-based programs in New York, California, and North Carolina. Participants were 12 years or older and seeking HIV testing, without known HIV infection. All participants with a negative rapid HIV test result were screened for acute HIV infection with an HIV Ag/Ab combination assay (index test) and pooled human immunodeficiency virus 1 (HIV-1) RNA testing. HIV RNA testing was the reference standard, with positive reference standard result defined as detectable HIV-1 RNA on an individual RNA test. Number and proportion with acute HIV infections detected. Among 86,836 participants with complete test results (median age, 29 years; 75.0% men; 51.8% men who have sex with men), established HIV infection was diagnosed in 1158 participants (1.33%) and acute HIV infection was diagnosed in 168 participants (0.19%). Acute HIV infection was detected in 134 participants with HIV Ag/Ab combination testing (0.15% [95% CI, 0.13%-0.18%]; sensitivity, 79.8% [95% CI, 72.9%-85.6%]; specificity, 99.9% [95% CI, 99.9%-99.9%]; positive predictive value, 59.0% [95% CI, 52.3%-65.5%]) and in 164 participants with pooled HIV RNA testing (0.19% [95% CI, 0.16%-0.22%]; sensitivity, 97.6% [95% CI, 94.0%-99.4%]; specificity, 100% [95% CI, 100%-100%]; positive predictive value, 96.5% [95% CI, 92.5%-98.7%]; sensitivity comparison, P < .001). Overall HIV Ag/Ab combination testing detected 82% of acute HIV infections detectable by pooled HIV RNA testing. Compared with rapid HIV testing alone, HIV Ag/Ab combination testing increased the relative HIV diagnostic yield (both established and acute HIV infections) by 10.4% (95% CI, 8.8%-12.2%) and pooled HIV RNA testing increased the relative HIV diagnostic yield by 12.4% (95% CI, 10.7%-14.3%). In a high-prevalence population, HIV screening using an HIV Ag/Ab combination assay following a negative rapid test detected 82% of acute HIV infections detectable by pooled HIV RNA testing, with a positive predictive value of 59%. Further research is needed to evaluate this strategy in lower-prevalence populations and in persons using preexposure prophylaxis for HIV prevention

Antiretroviral Therapy Initiated During Acute HIV Infection Fails to Prevent Persistent T-Cell Activation

Initiation of ART during acute HIV-1 infection may prevent persistent immune activation. We analyzed longitudinal CD38+HLA-DR+ CD8+ T cell percentages in 31 acutely infected individuals who started early (median 43 days since infection) and successful ART, and maintained viral suppression through 96 weeks. Pre-therapy a median of 72.6% CD8+ T cells were CD38+HLA-DR+, and while this decreased to 15.6% by 96 weeks, it remained substantially higher than seronegative controls (median 8.9%, p=0.008). Shorter time to suppression predicted lower activation at 96 weeks. These results support the hypothesis that very early events in HIV-1 pathogenesis may result in prolonged immune dysfunction

CD4+CD8+ T Cells Represent a Significant Portion of the Anti-HIV T Cell Response to Acute HIV Infection

Previous studies have revealed that HIV infected individuals possess circulating CD4+CD8+ (DP) T-cells specific for HIV antigens. In the present study, we analyzed the proliferation and functional profile of circulating DP T-cells from 30 acutely HIV infected individuals and 10 chronically HIV infected viral controllers. The acutely infected group had DP T-cells which showed more proliferative capability and multifunctionality than both their CD4+ and CD8+ T-cells. DP T-cells were found to exhibit greater proliferation and higher multifunctionality compared to CD4 T-cells in the viral controller group. The DP T-cell response represented 16% of the total anti-HIV proliferative response and greater than 70% of the anti-HIV multifunctional response in the acutely infected subjects. Proliferating DP T-cells of the acutely infected subjects responded to all HIV antigen pools with equal magnitude. Conversely, the multifunctional response was focused on the pool representing Nef, Rev, Tat, VPR and VPU. Meanwhile, the controllers’ DP T-cells focused on Gag and the Nef, Rev, Tat, VPR and VPU pool for both their proliferative and multifunctional responses. Finally, we show that the presence of proliferating DP T-cells following all HIV antigen stimulations is well correlated with proliferating CD4 T-cells while multifunctionality appears to be largely independent of multifunctionality in other T-cell compartments. Therefore, DP T-cells represent a highly reactive cell population during acute HIV infection, which responds independently from the traditional T-cell compartments

Incident Sexually Transmitted Infection as a Biomarker for High-Risk Sexual Behavior After Diagnosis of Acute HIV

Sexually transmitted infection (STI) diagnosis following diagnosis of acute HIV infection (AHI) indicates ongoing high-risk sexual behavior and possible risk of HIV transmission. We assessed predictors of STI acquisition and the effect of time since care entry on STI incidence in AHI patients in care and receiving consistent risk-reduction messaging

Precise Quantitation of the Latent HIV-1 Reservoir: Implications for Eradication Strategies

The quantitative viral outgrowth assay (QVOA) provides a precise minimal estimate of the reservoir of resting CD4+ T-cell infection (resting cell infection [RCI]). However, the variability of RCI over time during antiretroviral therapy (ART), relevant to assess potential effects of latency-reversing agents or other interventions, has not been fully described. We performed QVOA on resting CD4+ T cells obtained via leukapheresis from 37 human immunodeficiency virus (HIV)–infected patients receiving stable suppressive ART for a period of 6 years. Patients who started ART during acute (n = 17) or chronic (n = 20) HIV infection were studied once HIV RNA levels were 6-fold were rare. We suggest that a 6-fold decline is a relevant threshold to reliably identify effects of antilatency interventions on RCI