Immune-driven recombination and loss of control after HIV superinfection

Abstract

After acute HIV infection, CD8 + T cells are able to control viral replication to a set point. This control is often lost after superinfection, although the mechanism behind this remains unclear. In this study, we illustrate in an HLA-B27 + subject that loss of viral control after HIV superinfection coincides with rapid recombination events within two narrow regions of Gag and Env. Screening for CD8 + T cell responses revealed that each of these recombination sites ( ‫ف‬ 50 aa) encompassed distinct regions containing two immunodominant CD8 epitopes (B27-KK10 in Gag and Cw1-CL9 in Env). Viral escape and the subsequent development of variant-specifi c de novo CD8 + T cell responses against both epitopes were illustrative of the signifi cant immune selection pressures exerted by both responses. Comprehensive analysis of the kinetics of CD8 responses and viral evolution indicated that the recombination events quickly facilitated viral escape from both dominant WT-and variant-specifi c responses. These data suggest that the ability of a superinfecting strain of HIV to overcome preexisting immune control may be related to its ability to rapidly recombine in critical regions under immune selection pressure. These data also support a role for cellular immune pressures in driving the selection of new recombinant forms of HIV.

Dynamics of HIV Type 1 Recombination Following Superinfection

“…2,7-9 Fang et al 4 showed replacement of subtype A virus with AC, but did not show the presence of ''pure'' subtype C virus, so the superinfection could have been with an AC recombinant. Others have reported dual infection 10 or superinfection 3,5,6 with the same subtype followed by recombination. Koelsch et al 11 described complete replacement of drug-resistant virus with superinfecting wild-type virus, while Pingen et al 12 described complete replacement of wildtype virus with drug-resistant virus, but recombination was not detected in these reports.…”

“…However, superinfection may be difficult to detect when the superinfecting virus is of the same subtype as the initial virus, and the detection of possible consequent recombinants is restricted to a handful of reports. [2][3][4][5][6] It has previously been reported that superinfection with a virus of different subtype can result in replacement of the original virus. 2,7-9 Fang et al 4 showed replacement of subtype A virus with AC, but did not show the presence of ''pure'' subtype C virus, so the superinfection could have been with an AC recombinant.…”

Socioeconomic Impact of HIV/AIDS on Households under Free Antiretroviral Therapy in Preah Sihanouk Province, Cambodia

“…While the neutralizing antibody response was found to be low, a cellular response of this magnitude and breath did not translate into protection against the second HIV-1 strain even though its sequence only differed by 12%. Thus, these and additional well-documented cases demonstrated that superinfection can occur in the context of limited HIV-1-specific cytotoxic T cell responses mostly directed against a single epitope [10,35], yet it is not prevented by the presence of broad responses to multiple epitopes [9,11,34,39].…”

“…For instance, rapid generation of recombinant strains following HIV-1 superinfection might significantly enhance the ability of the newly produced virus to evade the immune system in controllers. Indeed, recombination events between the initial and the superinfecting HIV-1 strains within crucial regions targeted by HIV-1-specific CD8+ T cells led to viral escape and disease progression in one individual carrying the protective HLA-B27 allele [35].…”

“…Since then, multiple reported cases have described interclade [10,11,[23][24][25][26][27][28][29] as well as intraclade [9,[30][31][32][33][34][35] superinfections, but also triple superinfections [28,32,36], or superinfections involving substantially divergent strains belonging to the different HIV-1 and HIV-2 groups [37,38].…”