19 research outputs found
Rapid, complex adaption of transmitted HIV-1 full-length genomes in subtype C-infected individuals with differing disease progression.
CAPRISA 2013.Objective(s): There is limited information on full-length genome sequences and the
early evolution of transmitted HIV-1 subtype C viruses, which constitute the majority of
viruses spread in Africa. The purpose of this study was to characterize the earliest
changes across the genome of subtype C viruses following transmission, to better
understand early control of viremia.
Design: We derived the near full-length genome sequence responsible for clinical
infection from five HIV subtype C-infected individuals with different disease progression
profiles and tracked adaptation to immune responses in the first 6 months
of infection.
Methods: Near full-length genomes were generated by single genome amplification
and direct sequencing. Sequences were analyzed for amino acid mutations associated
with cytotoxic T lymphocyte (CTL) or antibody-mediated immune pressure, and for
reversion.
Results: Fifty-five sequence changes associated with adaptation to the new host were
identified, with 38% attributed to CTL pressure, 35% to antibody pressure, 16% to
reversions and the remainder were unclassified. Mutations in CTL epitopes were most
frequent in the first 5 weeks of infection, with the frequency declining over time with the
decline in viral load. CTL escape predominantly occurred in nef, followed by pol and
env. Shuffling/toggling of mutations was identified in 81% of CTL epitopes, with only
7% reaching fixation within the 6-month period.
Conclusion: There was rapid virus adaptation following transmission, predominantly
driven by CTL pressure, with most changes occurring during high viremia. Rapid escape
and complex escape pathways provide further challenges for vaccine protection
Neutralization profiles of HIV-1 viruses from the VRC01 Antibody Mediated Prevention (AMP) trials
The VRC01 Antibody Mediated Prevention (AMP) efficacy trials conducted between 2016 and 2020 showed for the first time that passively administered broadly neutralizing antibodies (bnAbs) could prevent HIV-1 acquisition against bnAb-sensitive viruses. HIV-1 viruses isolated from AMP participants who acquired infection during the study in the sub-Saharan African (HVTN 703/HPTN 081) and the Americas/European (HVTN 704/HPTN 085) trials represent a panel of currently circulating strains of HIV-1 and offer a unique opportunity to investigate the sensitivity of the virus to broadly neutralizing antibodies (bnAbs) being considered for clinical development. Pseudoviruses were constructed using envelope sequences from 218 individuals. The majority of viruses identified were clade B and C; with clades A, D, F and G and recombinants AC and BF detected at lower frequencies. We tested eight bnAbs in clinical development (VRC01, VRC07-523LS, 3BNC117, CAP256.25, PGDM1400, PGT121, 10–1074 and 10E8v4) for neutralization against all AMP placebo viruses (n = 76). Compared to older clade C viruses (1998–2010), the HVTN703/HPTN081 clade C viruses showed increased resistance to VRC07-523LS and CAP256.25. At a concentration of 1μg/ml (IC80), predictive modeling identified the triple combination of V3/V2-glycan/CD4bs-targeting bnAbs (10-1074/PGDM1400/VRC07-523LS) as the best against clade C viruses and a combination of MPER/V3/CD4bs-targeting bnAbs (10E8v4/10-1074/VRC07-523LS) as the best against clade B viruses, due to low coverage of V2-glycan directed bnAbs against clade B viruses. Overall, the AMP placebo viruses represent a valuable resource for defining the sensitivity of contemporaneous circulating viral strains to bnAbs and highlight the need to update reference panels regularly. Our data also suggests that combining bnAbs in passive immunization trials would improve coverage of global viruses
Neutralization profiles of HIV-1 viruses from the VRC01 Antibody Mediated Prevention (AMP) trials.
The VRC01 Antibody Mediated Prevention (AMP) efficacy trials conducted between 2016 and 2020 showed for the first time that passively administered broadly neutralizing antibodies (bnAbs) could prevent HIV-1 acquisition against bnAb-sensitive viruses. HIV-1 viruses isolated from AMP participants who acquired infection during the study in the sub-Saharan African (HVTN 703/HPTN 081) and the Americas/European (HVTN 704/HPTN 085) trials represent a panel of currently circulating strains of HIV-1 and offer a unique opportunity to investigate the sensitivity of the virus to broadly neutralizing antibodies (bnAbs) being considered for clinical development. Pseudoviruses were constructed using envelope sequences from 218 individuals. The majority of viruses identified were clade B and C; with clades A, D, F and G and recombinants AC and BF detected at lower frequencies. We tested eight bnAbs in clinical development (VRC01, VRC07-523LS, 3BNC117, CAP256.25, PGDM1400, PGT121, 10-1074 and 10E8v4) for neutralization against all AMP placebo viruses (n = 76). Compared to older clade C viruses (1998-2010), the HVTN703/HPTN081 clade C viruses showed increased resistance to VRC07-523LS and CAP256.25. At a concentration of 1μg/ml (IC80), predictive modeling identified the triple combination of V3/V2-glycan/CD4bs-targeting bnAbs (10-1074/PGDM1400/VRC07-523LS) as the best against clade C viruses and a combination of MPER/V3/CD4bs-targeting bnAbs (10E8v4/10-1074/VRC07-523LS) as the best against clade B viruses, due to low coverage of V2-glycan directed bnAbs against clade B viruses. Overall, the AMP placebo viruses represent a valuable resource for defining the sensitivity of contemporaneous circulating viral strains to bnAbs and highlight the need to update reference panels regularly. Our data also suggests that combining bnAbs in passive immunization trials would improve coverage of global viruses
Features of recently transmitted HIV-1 clade C viruses that impact antibody recognition : implications for active and passive immunization.
CAPRISA, 2016.Abstract available in PDF file
Differences in HIV-1 neutralization breadth in two geographically distinct cohorts in Africa.
CAPRISA, 2015.Abstract available in pdf