HIV-1 Superinfection Occurs Less Frequently Than Initial Infection in a Cohort of High-Risk Kenyan Women

Abstract

HIV superinfection (reinfection) has been reported in several settings, but no study has been designed and powered to rigorously compare its incidence to that of initial infection. Determining whether HIV infection reduces the risk of superinfection is critical to understanding whether an immune response to natural HIV infection is protective. This study compares the incidence of initial infection and superinfection in a prospective seroincident cohort of high-risk women in Mombasa, Kenya. A next-generation sequencing-based pipeline was developed to screen 129 women for superinfection. Longitudinal plasma samples at <6 months, >2 years and one intervening time after initial HIV infection were analyzed. Amplicons in three genome regions were sequenced and a median of 901 sequences obtained per gene per timepoint. Phylogenetic evidence of polyphyly, confirmed by pairwise distance analysis, defined superinfection. Superinfection timing was determined by sequencing virus from intervening timepoints. These data were combined with published data from 17 additional women in the same cohort, totaling 146 women screened. Twenty-one cases of superinfection were identified for an estimated incidence rate of 2.61 per 100 person-years (pys). The incidence rate of initial infection among 1910 women in the same cohort was 5.75 per 100pys. Andersen-Gill proportional hazards models were used to compare incidences, adjusting for covariates known to influence HIV susceptibility in this cohort. Superinfection incidence was significantly lower than initial infection incidence, with a hazard ratio of 0.47 (CI 0.29–0.75, p = 0.0019). This lower incidence of superinfection was only observed >6 months after initial infection. This is the first adequately powered study to report that HIV infection reduces the risk of reinfection, raising the possibility that immune responses to natural infection are partially protective. The observation that superinfection risk changes with time implies a window of protection that coincides with the maturation of HIV-specific immunity.

Limited HIV-1 Superinfection in Seroconverters from the CAPRISA 004 Microbicide Trial

“…To date, these three studies are the largest in Africa to have used deep sequencing to examine for superinfection, and they were distinctly different in terms of rates of primary infections and follow-up. The rate of primary infection in the Rakai study (1.2/ 100 py), which included men and women, was substantially less than those within the CAPRISA 004 trial (7.3/100 py) and the Kenyan trial (5.75/100 py) (2,6,9). The study presented here and the Rakai study calculated IRRs in a similar manner, while the Kenyan study utilized a slightly different hazard ratio analysis (2, 6).…”

“…While individuals in the Rakai community cohort study were followed annually, seroconverters from the CAPRISA 004 study were followed up at least once per month until 12 months postinfection and every 3 months thereafter until ART initiation, and they continued to receive counseling at each visit. The Kenyan study collected samples quarterly, but the women were seen monthly (6,15). It is possible that the continuous reinforcement provided by these frequent visits affected the behavior of the women, which lowered their risk of SI.…”

“…The rates at which HIV SI occurs differ between populations and appear to be related, in part, to the underlying primary HIV incidence rate (2)(3)(4)(5). Previous analysis of high-risk women in Kenya found a significantly lower rate of SI compared to primary incidence (6). HIV SI can significantly impact HIV disease markers by increasing the HIV viral load temporarily or lastingly, by possibly accelerating disease progression, and by putatively increasing HIV-specific antibody responses (3,4,7,8).…”

Association between Cellular Immune Activation, Target Cell Frequency, and Risk of Human Immunodeficiency Virus Type 1 Superinfection

“…Some immune responses may even enhance infection risk, particularly if they increase recruitment of HIV-1 target cells to sites of viral entry without containing early replication. Our finding that an increased frequency of HIV-1 primary target cells is associated with increased odds of a second infection may partially explain the observation that the risk of superinfection appears to be highest in the first 6 months following initial infection (44,45), before target cell depletion. A strength of this study is the fact that superinfection cases were prospectively identified, allowing us to evaluate immunity in matched individuals with similar risk behaviors for exposure to HIV-1 but different outcomes.…”

A critical question for HIV vaccine development: Which antibodies to induce?

“…For instance, superinfected individuals had lower levels of cross-protective and autologous neutralizing Abs than the nonsuperinfected case-controls (33, 34). Although some studies are contradictory to these (35, 36), and other data suggest that cytotoxic T lymphocytes are capable of imposing selective pressure on HIV (37), results from a recent adequately powered study demonstrated that a first HIV infection reduces the risk of a subsequent infection by ~50% in high-risk Kenyan women (38). Additional evidence for the protective role of Abs comes from studies of maternal-fetal transmission.…”