V2-Specific Antibodies in HIV-1 Vaccine Research and Natural Infection: Controllers or Surrogate Markers

Abstract

Most human immunodeficiency virus (HIV) vaccine trials have lacked efficacy and empirical vaccine lead targets are scarce. Thus far, the only independent correlate of reduced risk of HIV-1 acquisition in humans is elevated levels of V2-specific antibodies identified in the modestly protective RV144 vaccine trial. Ten years after RV144, human and non-human primate vaccine studies have reassessed the potential contribution of V2-specific antibodies to vaccine efficacy. In addition, studies of natural HIV-1 infection in humans have provided insight into the development of V1V2-directed antibody responses and their impact on clinical parameters and disease progression. Functionally diverse anti-V2 monoclonal antibodies were isolated and their structurally distinct V2 epitope regions characterized. After RV144, a plethora of research studies were performed using different model systems, immunogens, protocols, and challenge viruses. These diverse studies failed to provide a clear picture regarding the contribution of V2 antibodies to vaccine efficacy. Here, we summarize the biological functions and clinical findings associated with V2-specific antibodies and discuss their impact on HIV vaccine research.

SARS-CoV-2 Portrayed Against HIV: Contrary Viral Strategies in Similar Disguise

“…This strategy is currently tested in human clinical trials [180,181]. However, while vaccines can induce sufficiently potent bnAbs against SARS-CoV-2 [182][183][184], and COVID-19 convalescent individuals acquire protective immunity through natural infection [185], it has not been possible to induce broadly protective Abs by HIV-1 vaccines [76] and primary HIV-1 infection does not adequately protect from superinfection [186][187][188]. Ab responses induced in participants of HIV-1 human vaccine trials such as RV144 were mostly non-or weakly neutralizing, waned rapidly, and/or suffered from rapid viral escape (see 4.3) [76,81,189,190].…”

“…Indeed, Fc-mediated cellular responses such as ADCC and ADCP have been associated with protection from HIV-1 disease progression and protection from (S)HIV infection in animal models or in a human vaccine trial [76,219,223,224]. For example, ADCC responses in the presence of low plasma IgA/IgG ratios correlated with protection from infection in a large human vaccine trial with partial efficacy (RV144) [81,190,[225][226][227], yet a complete mechanistic explanation remains elusive [76,219]. Furthermore, Fcγ-phenotyping in vaccinees of the same trial revealed that distinct single-nucleotide polymorphisms (SNP) in the FCγR2C gene conferred 91% vaccine efficacy against HIV-1 carrying immunodominant epitopes in Env that experienced vaccine selection pressure.…”

Search for antiviral functions of potentially protective antibodies against V2 region of HIV-1

“…In rhesus macaque protection experiments, ADCC and ADCP correlated with the reduced acquisition of either SHIV or SIV infection in only two of 15 experiments analyzed. 20 , 22 , 49 Passive transfer of non-neutralizing mAbs specific to V2, CD4bs, C1 region of gp120, and gp41 HIV-1 to rhesus macaques in four different experiments probably mediated the Fc-induced activities, both ADCC and ADCP, due to the Abs’ binding properties, but was not able to prevent SHIV infection. 41 – 44 …”

Frequent and Durable Anti-HIV Envelope VIV2 IgG Responses Induced by HIV-1 DNA Priming and HIV-MVA Boosting in Healthy Tanzanian Volunteers

“…Sieve analysis suggested that V1V2 antibodies are capable of selectively blocking specific HIV-1 variants, further supporting vaccine-induced V2 responses as having a preventive role [ 14 ]. Additionally, V1V2-specific monoclonal antibodies have been correlated with control or protection from HIV, SIV and SHIV [ 15 , 16 ].…”