Potent Autologous and Heterologous Neutralizing Antibody Responses Occur in HIV-2 Infection across a Broad Range of Infection Outcomes

Abstract

Few studies have explored the role of neutralizing antibody (NAb) responses in controlling HIV-2 viremia and disease progression. Using a TZM-bl neutralization assay, we assessed heterologous and autologous NAb responses from a community cohort of HIV-2-infected individuals with a broad range of disease outcomes in rural Guinea-Bissau. All subjects (n = 40) displayed exceptionally high heterologous NAb titers (50% inhibitory plasma dilution or 50% inhibitory concentration [IC(50)], 1:7,000 to 1:1,000,000) against 5 novel primary HIV-2 envelopes and HIV-2 7312A, whereas ROD A and 3 primary envelopes were relatively resistant to neutralization. Most individuals also showed high autologous NAb against contemporaneous envelopes (78% of plasma-envelope combinations in 69 envelopes from 21 subjects), with IC(50)s above 1:10,000. No association between heterologous or autologous NAb titer and greater control of HIV-2 was found. A subset of envelopes was found to be more resistant to neutralization (by plasma and HIV-2 monoclonal antibodies). These envelopes were isolated from individuals with greater intrapatient sequence diversity and were associated with changes in potential N-linked glycosylation sites but not CD4 independence or CXCR4 use. Plasma collected from up to 15 years previously was able to potently neutralize recent autologous envelopes, suggesting a lack of escape from NAb and the persistence of neutralization-sensitive variants over time, despite significant NAb pressure. We conclude that despite the presence of broad and potent NAb responses in HIV-2-infected individuals, these are not the primary forces behind the dichotomous outcomes observed but reveal a limited capacity for adaptive selection and escape from host immunity in HIV-2 infection.

Sequential Evolution and Escape from Neutralization of Simian Immunodeficiency Virus SIVsmE660 Clones in Rhesus Macaques

“…While titers against subtype B HIV-1 Envs tend to remain at moderate levels, there are subtype differences, since early autologous neutralizing antibody responses are quite high in subtype C HIV-1 infection (37). Interestingly, several studies have recently demonstrated that NAb responses are very potent in HIV-2-infected cohorts, with NAb titers ranging from 10 4 to 10 6 per ml (13,26), levels which are similar to titers in the SIVsmE660-infected macaques in this study. While some studies suggest that HIV-2 does not escape NAb as effectively as HIV-1, a study by de Silva et al demonstrated a similar pattern of envelope evolution and the development of neutralization resistance (13).…”

“…Interestingly, several studies have recently demonstrated that NAb responses are very potent in HIV-2-infected cohorts, with NAb titers ranging from 10 4 to 10 6 per ml (13,26), levels which are similar to titers in the SIVsmE660-infected macaques in this study. While some studies suggest that HIV-2 does not escape NAb as effectively as HIV-1, a study by de Silva et al demonstrated a similar pattern of envelope evolution and the development of neutralization resistance (13). Compared with HIV-1-infected cohorts, disease progression during HIV-2 infection is usually slower and plasma viral loads are lower, suggesting that the potent NAb response may contribute to the delayed disease progression.…”

Heterogeneity in Neutralization Sensitivities of Viruses Comprising the Simian Immunodeficiency Virus SIVsmE660 Isolate and Vaccine Challenge Stock

“…Depending on the in vivo properties of these plateau viruses, SIVsmE660 is comprised of 65 to 90% highly neutralization-sensitive viruses with a minority population of more resistant viruses. Of note, two of the HIV-2 studies described above also identified heterogeneity within the HIV-2 Env clones they studied; the vast majority were highly sensitive tier 1-like Envs, while a minority were highly resistant tier-3 like Envs (39,95). This dichotomy of neutralization sensitivity, without representation of the intermediate-sensitivity tier 2-like Envs that predominate in HIV-1 infection, highlights still-unexplained differences in Env biology and Env-antibody interactions between HIV-2 and HIV-1.…”

“…It is interesting, though not entirely unexpected given their common origin and degree of genetic homology (9,13,14,16), to note the extent to which the SIVsmE660 and HIV-2 neutralization profiles overlap. Three recent studies of the antibody response to HIV-2 infection independently demonstrated that HIV-2-infected individuals mount high-titer, broadly reactive NAb responses (39,95,96). Similar to the uncloned SIVsmE660 isolate and Envs described here, the majority of primary HIV-2 strains, including SGA-derived Envs, were highly sensitive to antibody-mediated neutralization through multiple exposed epitopes (V3, CD4i, CD4bs, and V4), suggesting that SIVsmE660 and HIV-2 have more open, flexible Env conformations, akin to those of lab-adapted HIV-1 strains and distinct from those of primary HIV-1 isolates and T/F viruses (39).…”

“…We also demonstrated that the uncloned isolate possesses a minor fraction of substantially more resistant viruses, and this dichotomy could have unanticipated effects on the outcome of low-dose SIVsmE660 challenge studies in terms of both disease natural history and vaccine-elicited immune protection by Env antibodies. While these features of the SIVsmE660-rhesus infection model distinguish it from HIV-1 infection in humans, they have interesting and still-unexplained parallels with HIV-2 infection of humans (39,95,96). The converse of these features of SIVsmE660 and HIV-2 neutralization sensitivity is the property of pan-neutralization resistance of SIVmac251 and SIVmac239, which mechanistically remains largely unexplained (17)(18)(19)100).…”