Multiple HIV-1-specific IgG3 responses decline during acute HIV-1: implications for detection of incident HIV infection

Different HIV-1 antigen specificities appear in sequence after HIV-1 transmission and the immunoglobulin G (IgG) subclass responses to HIV antigens are distinct from each other. The initial predominant IgG subclass response to HIV-1 infection consists of IgG1 and IgG3 antibodies with a noted decline in some IgG3 antibodies during acute HIV-1 infection. Thus, we postulate that multiple antigen-specific IgG3 responses may serve as surrogates for the relative time since HIV-1 acquisition

Initial antibodies binding to HIV-1 gp41 in acutely infected subjects are polyreactive and highly mutated

Many HIV-1 envelope-reactive antibodies shortly after HIV-1 transmission may arise from crow-reactive memory B cells previously stimulated by non-HIV-1 host or microbial antigen

Polyclonal B Cell Differentiation and Loss of Gastrointestinal Tract Germinal Centers in the Earliest Stages of HIV-1 Infection

The antibody response to HIV-1 does not appear in the plasma until approximately 2–5 weeks after transmission, and neutralizing antibodies to autologous HIV-1 generally do not become detectable until 12 weeks or more after transmission. Moreover, levels of HIV-1–specific antibodies decline on antiretroviral treatment. The mechanisms of this delay in the appearance of anti-HIV-1 antibodies and of their subsequent rapid decline are not known. While the effect of HIV-1 on depletion of gut CD4+ T cells in acute HIV-1 infection is well described, we studied blood and tissue B cells soon after infection to determine the effect of early HIV-1 on these cells

Computational analysis of antibody dynamics identifies recent HIV-1 infection.

CAPRISA, 2017.Abstract available in pdf

Pentavalent HIV-1 vaccine protects against simian-human immunodeficiency virus challenge

The RV144 Thai trial HIV-1 vaccine of recombinant poxvirus (ALVAC) and recombinant HIV-1 gp120 subtype B/subtype E (B/E) proteins demonstrated 31% vaccine efficacy. Here we design an ALVAC/Pentavalent B/E/E/E/E vaccine to increase the diversity of gp120 motifs in the immunogen to elicit a broader antibody response and enhance protection. We find that immunization of rhesus macaques with the pentavalent vaccine results in protection of 55% of pentavalent-vaccine-immunized macaques from simian–human immunodeficiency virus (SHIV) challenge. Systems serology of the antibody responses identifies plasma antibody binding to HIV-infected cells, peak ADCC antibody titres, NK cell-mediated ADCC and antibody-mediated activation of MIP-1β in NK cells as the four immunological parameters that best predict decreased infection risk that are improved by the pentavalent vaccine. Thus inclusion of additional gp120 immunogens to a pox-prime/protein boost regimen can augment antibody responses and enhance protection from a SHIV challenge in rhesus macaques

Strain-Specific V3 and CD4 Binding Site Autologous HIV-1 Neutralizing Antibodies Select Neutralization-Resistant Viruses.

The third variable (V3) loop and the CD4 binding site (CD4bs) of the HIV-1 envelope are frequently targeted by neutralizing antibodies (nAbs) in infected individuals. In chronic infection, HIV-1 escape mutants repopulate the plasma, and V3 and CD4bs nAbs emerge that can neutralize heterologous tier 1 easy-to-neutralize but not tier 2 difficult-to-neutralize HIV-1 isolates. However, neutralization sensitivity of autologous plasma viruses to this type of nAb response has not been studied. We describe the development and evolution in vivo of antibodies distinguished by their target specificity for V3 and CD4bs epitopes on autologous tier 2 viruses but not on heterologous tier 2 viruses. A surprisingly high fraction of autologous circulating viruses was sensitive to these antibodies. These findings demonstrate a role for V3 and CD4bs antibodies in constraining the native envelope trimer in vivo to a neutralization-resistant phenotype, explaining why HIV-1 transmission generally occurs by tier 2 neutralization-resistant viruses

Strain-Specific V3 and CD4 Binding Site Autologous HIV-1 Neutralizing Antibodies Select Neutralization-Resistant Viruses

The third variable (V3) loop and the CD4 binding site (CD4bs) of the HIV-1 envelope are frequently targeted by neutralizing antibodies (nAbs) in infected individuals. In chronic infection, HIV-1 escape mutants repopulate the plasma, and V3 and CD4bs nAbs emerge that can neutralize heterologous tier 1 easy-to-neutralize, but not tier 2 difficult-to-neutralize HIV-1 isolates. However, neutralization sensitivity of autologous plasma viruses to this type of nAb response has not been studied. We describe the development and evolution in vivo of antibodies distinguished by their target specificity for V3and CD4bs epitopes on autologous tier 2 viruses but not on heterologous tier 2 viruses. A surprisingly high fraction of autologous circulating viruses was sensitive to these antibodies. These findings demonstrate a role for V3 and CD4bs antibodies in constraining the native envelope trimer in vivo to a neutralization-resistant phenotype, explaining why HIV-1 transmission generally occurs by tier 2 neutralization-resistant viruses

Additional file 1 of Performance of model-based vs. permutation tests in the HEALing (Helping to End Addiction Long-termSM) Communities Study, a covariate-constrained cluster randomized trial

Additional file 1: Supplementary Table 1. Distribution of number of opioid overdose deaths from 5,000 simulations across 67 communities in the HCS*. Supplementary Table 2. Type I error rate for the Model-Based and Permutation Tests from the unadjusted model for the HEALing Communities Study Design, Overall (4 States) and for the subgroup analysis of Massachusetts. Supplementary Table 3. Power for the Model-Based and Permutation Tests from the unadjusted model to Detect Various Differences Between Groups in Number of Opioid Overdose Deaths. Supplementary Table 4. Type I error rate for the Model-Based and Permutation Tests from the fully adjusted model removing Urban/Rural as the covariate for the HEALing Communities Study Design, Overall (4 States) and for the subgroup analysis of Massachusetts. Supplementary Table 5. Power for the Model-Based and Permutation Tests from the fully adjusted model removing Urban/Rural as the covariate to Detect Various Differences Between Groups in Number of Opioid Overdose Deaths. Supplementary Table 6. Type I error rate for the Model-Based and Permutation Tests from the fully adjusted model removing baseline death rates as the covariate for the HEALing Communities Study Design, Overall (4 States) and for the subgroup analysis of Massachusetts. Supplementary Table 7. Power for the Model-Based and Permutation Tests from the fully adjusted model removing baseline death rates as the covariate to Detect Various Differences Between Groups in Number of Opioid Overdose Deaths. Supplementary Table 8. Type I error rate for the Model-Based and Permutation Tests for the HEALing Communities Study Design, Overall (4 States) and for the subgroup analysis of Massachusetts for different random allocations. Supplementary Table 9. Power for the Model-Based and Permutation Tests to Detect Various Differences Between Groups in Number of Opioid Overdose Deaths for different random allocations. Supplementary Text 1