Infection by Discordant Strains of HIV-1 Markedly Enhances the Neutralizing Antibody Response against Heterologous Virus

Abstract

High-risk cohorts in East Africa and the United States show rates of dual HIV-1 infection-the concomitant or sequential infection by two HIV-1 strains-of 50% to 100% of those of primary infection, and our normalrisk HIV-positive cohort in Cameroon exhibits a rate of dual infection of 11% per year, signifying that these infections are not exceptional. Little is known regarding the effect of dual infections on host immunity, despite the fact that they provide unique opportunities to investigate how the immune response is affected when challenged with diverse HIV-1 antigens. Using heterologous primary isolates, we have shown here that dual HIV-1 infection by genetically distant strains correlates with significantly increased potency and breadth of the anti-HIV-1 neutralizing antibody response. When the neutralization capacities of sequential plasma obtained before and after the dual infection of 4 subjects were compared to those of matched plasma obtained from 23 singly infected control subjects, a significant increase in the neutralization capacity of the sequential sample was found for 16/28 dually infected plasma/virus pairs, while only 4/159 such combinations for the control subjects exhibited a significant increase (P < 0.0001). Similarly, there was a significant increase in the plasma dilution capable of neutralizing 50% of virus (IC 50 ) for 18/24 dually infected plasma/virus pairs, while 0/36 controls exhibited such an increase (P < 0.0001). These results demonstrate that dual HIV-1 infection broadens and strengthens the anti-HIV-1 immune response, suggesting that vaccination schemes that include polyvalent, genetically divergent immunogens may generate highly protective immunity against any HIV-1 challenge strain.

Potent and Broad Neutralization of HIV-1 Subtype C by Plasma Antibodies Targeting a Quaternary Epitope Including Residues in the V2 Loop

“…Another factor that has been implicated in the development of breadth is HIV-1 sequence diversity, with individuals with greater envelope diversity early in infection developing greater breadth during chronic infection (30). This observation is supported by recent data showing that dual infection results in broader and more potent nAb responses (31). CAP256 was superinfected in the window between the initial infection and the development of autologous nAb responses, and recombination between the two infecting strains resulted in substantial viral variation over the first year of infection (data not shown).…”

Multiple Pathways of Escape from HIV Broadly Cross-Neutralizing V2-Dependent Antibodies

“…Two recent studies have shown that superinfection resulted in greater neutralizing breadth and potency (46,47). In one of these studies, broad and potent NAb responses developed in 2 elite neutralizers very soon after infection with a second virus, suggesting that the development of breadth was accelerated through superinfection (46).…”

“…Whether a similar situation provoked the exceptional breadth in CAP256 is unknown. It is possible that superinfection with a discordant virus results in the broadening of the NAb response to multiple epitopes presented on discordant viruses (48), a model supported by the fact that greatest breadth was associated with intersubtype superinfection (46,47). It is also possible that superinfection focuses the NAb response onto conserved epitopes common to both infecting viruses.…”

How Can HIV-Type-1-Env Immunogenicity Be Improved to Facilitate Antibody-Based Vaccine Development?

“…The evidence, though inconclusive, is not encouraging. The incidence of superinfection varies from 50% to 100% of the primary-infection rate in uninfected control cohorts, [22][23][24] and superinfection occurs in the face of substantial crossneutralizing titers, also specifically against early posttransmission forms of the virus. 22 However, the minority of subjects with broad and strong NAb responses may be too small to make a detectable impact, and the NAb titers may even more rarely reach the high levels found experimentally to be required for protection.…”