RV144 vaccine imprinting constrained HIV-1 evolution following breakthrough infection.

The scale of the HIV-1 epidemic underscores the need for a vaccine. The multitude of circulating HIV-1 strains together with HIV-1's high evolvability hints that HIV-1 could adapt to a future vaccine. Here, we wanted to investigate the effect of vaccination on the evolution of the virus post-breakthrough infection.

Dynamics of Human Immunodeficiency Virus-1 Genetic Diversification During Acute Infection.

We analyzed human immunodeficiency virus envelope diversity in 98 acute infections. The within-host genetic diversity, divergence from transmitted/founder (T/F) strain, and the observed frequency of multiple T/F infections increased with Fiebig stage. These data identify rapid viral dynamics during acute infection with implications for clinical trials conducted in this setting.

Factors influencing estimates of HIV-1 infection timing using BEAST.

While large datasets of HIV-1 sequences are increasingly being generated, many studies rely on a single gene or fragment of the genome and few comparative studies across genes have been done. We performed genome-based and gene-specific Bayesian phylogenetic analyses to investigate how certain factors impact estimates of the infection dates in an acute HIV-1 infection cohort, RV217. In this cohort, HIV-1 diagnosis corresponded to the first RNA positive test and occurred a median of four days after the last negative test, allowing us to compare timing estimates using BEAST to a narrow window of infection.

RV144 HIV-1 vaccination impacts post-infection antibody responses.

The RV144 vaccine efficacy clinical trial showed a reduction in HIV-1 infections by 31%. Vaccine efficacy was associated with stronger binding antibody responses to the HIV Envelope (Env) V1V2 region, with decreased efficacy as responses wane. High levels of Ab-dependent cellular cytotoxicity (ADCC) together with low plasma levels of Env-specific IgA also correlated with decreased infection risk.

Novel monoclonal antibodies to the SERINC5 HIV-1 restriction factor detect endogenous andvirion-associated SERINC5.

SERINC5 is a multi-pass transmembrane protein that is thought to play a role in serine incorporation during cellular membrane biosynthesis. This protein has also been identified as a human immunodeficiency virus Type 1 (HIV-1) restriction factor. The paucity of monoclonal antibodies (mAbs) against SERINC5 has posed a challenge for the study of the endogenous protein.

Neutralizing antibody VRC01 failed to select for HIV-1 mutations upon viral rebound.

Infusion of the broadly neutralizing antibody VRC01 has been evaluated in individuals chronically infected with HIV-1. Here, we studied how VRC01 infusions affected viral rebound after cessation of antiretroviral therapy (ART) in 18 acutely treated and durably suppressed individuals. Viral rebound occurred in all individuals, yet VRC01 infusions modestly delayed rebound and participants who showed a faster decay of VRC01 in serum rebounded more rapidly.

Molecular dating and viral load growth rates suggested that the eclipse phase lasted about a week in HIV-1 infected adults in East Africa and Thailand.

Most HIV-1 infected individuals do not know their infection dates. Precise infection timing is crucial information for studies that document transmission networks or drug levels at infection. To improve infection timing, we used the prospective RV217 cohort where the window when plasma viremia becomes detectable is narrow: the last negative visit occurred a median of four days before the first detectable HIV-1 viremia with an RNA test, referred below as diagnosis.

A vaccine-induced gene expression signature correlates with protection against SIV and HIV in multiple trials.

Current HIV vaccines are only partially efficacious, presenting an opportunity to identify correlates of protection and, thereby, potential insight into mechanisms that prevent HIV acquisition. Two independent preclinical challenge studies in nonhuman primates (NHPs) previously showed partial efficacy of a mosaic adenovirus 26 (Ad26)-based HIV-1 vaccine candidate. To investigate the basis of this protection, we performed whole transcriptomics profiling by RNA sequencing (RNA-seq) in sorted lymphocytes from peripheral blood samples taken during these studies at different time points after vaccination but before challenge.

Deep Sequencing Reveals Central Nervous System Compartmentalization in Multiple Transmitted/Founder Virus Acute HIV-1 Infection.

HIV-1 disseminates to a broad range of tissue compartments during acute HIV-1 infection (AHI). The central nervous system (CNS) can serve as an early and persistent site of viral replication, which poses a potential challenge for HIV-1 remission strategies that target the HIV reservoir. CNS compartmentalization is a key feature of HIV-1 neuropathogenesis.

New Subtype B Containing HIV-1 Circulating Recombinant of sub-Saharan Africa Origin in Nigerian Men Who Have Sex With Men.

Background: HIV-1 circulating recombinant forms (CRF) containing subtype B are uncommon in sub-Saharan Africa. Prevalent infections observed during enrollment of a prospective study of men who have sex with men (MSM) from Lagos, Nigeria, revealed the presence of a family of subtype B and CRF02_AG recombinants. This report describes the HIV-1 genetic diversity within a high-risk, high-prevalence, and previously undersampled cohort of Nigerian MSM.

Atovaquone/proguanil therapy for Plasmodium falciparum and Plasmodium vivax malaria in Indonesians who lack clinical immunity.

Thirty-eight of 295 subjects participating in a randomized, double-blind, placebo-controlled trial of the efficacy of daily administration of atovaquone/proguanil for malaria prevention developed malaria at some time during the 20-week prophylaxis period. These subjects (3 atovaquone/proguanil recipients and 35 placebo recipients) were treated with 4 tablets of atovaquone/proguanil per day for 3 days. Atovaquone/proguanil provided safe, well-tolerated, and effective therapy for uncomplicated malaria in nonimmune Indonesians.

Randomized, placebo-controlled trial of atovaquone/proguanil for the prevention of Plasmodium falciparum or Plasmodium vivax malaria among migrants to Papua, Indonesia.

The increasing prevalence of resistance to antimalarial drugs reduces options for malaria prophylaxis. Atovaquone/proguanil (Malarone; GlaxoSmithKline) has been >95% effective in preventing Plasmodium falciparum malaria in lifelong residents of areas of holoendemicity, but data from persons without clinical immunity or who are at risk for Plasmodium vivax malaria have not been described. We conducted a randomized, double-blinded study involving 297 people from areas of nonendemicity in Indonesia who migrated to Papua (where malaria is endemic) < or =26 months before the study period.

Absence of antigenic competition in Aotus monkeys immunized with Plasmodium falciparum DNA vaccines delivered as a mixture.

Aotus lemurinus lemurinus monkeys were immunized four times with one of three DNA plasmids expressing important Plasmodium falciparum blood stage vaccine candidate proteins or with a mixture containing all three vaccines. The three vaccines encoded sequences from apical merozoite antigen-1 (AMA-1), erythrocyte binding protein-175 (EBA-175) and merozoite surface protein-1 (MSP-1). Antigen-specific enzyme-linked immunosorbant assays (ELISAs) showed no significant differences in antibody titer induced to the three antigens by a single vaccine compared with the titer induced to that same antigen by the trivalent preparation.