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A mainstay of strategies to prevent HIV-1 transmission is to use antiretroviral therapy (ART) for pre-exposure prophylaxis (PrEP). Critical to the design and interpretation of PrEP prevention trials is the ability to make accurate pharmacological measurements of ART drugs in human genital and colorectal mucosal tissues, the principal route of HIV transmission. Here, we evaluated two drugs that are preferentially used for PrEP: tenofovir (TFV) disoproxil fumarate (TDF) and emtricitabine (FTC). A single oral dose of TDF/FTC (Truvada) was administered to 15 healthy individuals. Over the next 14 days, TFV and FTC were measured in blood plasma and genital secretions using a sensitive assay (lower level of quantification, 0.1 ng/ml). The active intracellular phosphorylated metabolites of these drugs [TFV diphospate (TFV-DP) and FTC triphosphate (FTC-TP)] were measured in homogenates prepared from rectal, vaginal, and cervical tissues. TFV and FTC were detected in blood plasma 14 days after administration of a single dose. The area under the concentration-time curve from 24 hours to 14 days (AUC1–14d) for FTC in genital secretions was 27-fold greater than in blood plasma, whereas the AUC1–14d for TFV was only 2.5-fold greater in genital secretions than in blood plasma. In rectal tissue, TFV and TFV-DP concentrations were detectable for 14 days and were 100-fold higher than the concentrations in vaginal and cervical tissues. Vaginal and cervical tissue concentrations of FTC were 10- to 15-fold higher than in rectal tissue. Despite high concentrations of FTC in vaginal and cervical tissue, FTC-TP concentrations in all tissue types were detected for only 2 days after dose. The exposure to TFV, TFV-DP, FTC, and FTC-TP was wide ranging depending on the type of mucosal tissue. These results demonstrate the need for detailed pharmacological studies to improve the application of ART for PrEP to prevent transmission of HIV.

Understanding the interactions between human immunodeficiency virus type 1 (HIV-1) virions and antibodies (Ab) produced during acute HIV-1 infection (AHI) is critical for defining antibody antiviral capabilities. Antibodies that bind virions may prevent transmission by neutralization of virus or mechanically prevent HIV-1 migration through mucosal layers. In this study, we quantified circulating HIV-1 virion-immune complexes (ICs), present in approximately 90% of AHI subjects, and compared the levels and antibody specificity to those in chronic infection. Circulating HIV-1 virions coated with IgG (immune complexes) were in significantly lower levels relative to the viral load in acute infection than in chronic HIV-1 infection. The specificities of the antibodies in the immune complexes differed between acute and chronic infection (anti-gp41 Ab in acute infection and anti-gp120 in chronic infection), potentially suggesting different roles in immunopathogenesis for complexes arising at different stages of infection. We also determined the ability of circulating IgG from AHI to bind infectious versus noninfectious virions. Similar to a nonneutralizing anti-gp41 monoclonal antibody (MAb), purified plasma IgG from acute HIV-1 subjects bound both infectious and noninfectious virions. This was in contrast to the neutralizing antibody 2G12 MAb that bound predominantly infectious virions. Moreover, the initial antibody response captured acute HIV-1 virions without selection for different HIV-1 envelope sequences. In total, this study demonstrates that the composition of immune complexes are dynamic over the course of HIV-1 infection and are comprised initially of antibodies that nonselectively opsonize both infectious and noninfectious virions, likely contributing to the lack of efficacy of the antibody response during acute infection.

The precise identification of the HIV-1 envelope glycoprotein (Env) responsible for productive clinical infection could be instrumental in elucidating the molecular basis of HIV-1 transmission and in designing effective vaccines. Here, we developed a mathematical model of random viral evolution and, together with phylogenetic tree construction, used it to analyze 3,449 complete env sequences derived by single genome amplification from 102 subjects with acute HIV-1 (clade B) infection. Viral env genes evolving from individual transmitted or founder viruses generally exhibited a Poisson distribution of mutations and star-like phylogeny, which coalesced to an inferred consensus sequence at or near the estimated time of virus transmission. Overall, 78 of 102 subjects had evidence of productive clinical infection by a single virus, and 24 others had evidence of productive clinical infection by a minimum of two to five viruses. Phenotypic analysis of transmitted or early founder Envs revealed a consistent pattern of CCR5 dependence, masking of coreceptor binding regions, and equivalent or modestly enhanced resistance to the fusion inhibitor T1249 and broadly neutralizing antibodies compared with Envs from chronically infected subjects. Low multiplicity infection and limited viral evolution preceding peak viremia suggest a finite window of potential vulnerability of HIV-1 to vaccine-elicited immune responses, although phenotypic properties of transmitted Envs pose a formidable defense.