Year Of Primary Infection Research Articles

Interferon-induced transmembrane protein-3 rs12252-C is associated with rapid progression of acute HIV-1 infection in Chinese MSM cohort.

Background:The interferon-inducible transmembrane protein-3 (IFITM3) is a protein that restricts multiple pathogenic viruses such as influenza virus. The single-nucleotide polymorphism rs12252-C, which is rare in Caucasian populations, but much more common in the Han Chinese population, has been found in much higher homozygous frequency in patients with severe acute influenza. Until now, there has been no study on the effect of this genetic variant on the clinical control of other viral infections.Objectives:To investigate the impact of IFITM3-rs12252 genotypes on primary HIV-1 infection progression in an acute HIV-1-infected cohort in Beijing (PRIMO), China.Design and methods:We identified IFITM3-rs12252 genotypes of 178 acute HIV-1-infected patients and 196 HIV-negative candidates from the PRIMO cohort. HIV-1 viral load and CD4+ T-cell counts were monitored at multiple time points during the first year of infection, and the association between IFITM3-rs12252 genotype and disease progression was evaluated.Results:The current study shows that the IFITM3-rs12252 genetic variant affects the progression of HIV-1 infection, but not the acquisition. A significantly higher frequency of the CC/CT genotypes was found in rapid progressors compared to nonprogressors. Patients with CC/CT genotypes showed an elevated peak viremia level and significantly lower CD4+ T-cell count at multiple time points during the first year of primary infection, and a significantly higher risk of rapid decline of the CD4+ T-cell count to below 350 cells/μl.Conclusion:A novel association between IFITM3 gene polymorphism and rapid disease progression is reported in an acute HIV-1-infected MSM cohort in China.

HIV-1 subtype C superinfected individuals mount low autologous neutralizing antibody responses prior to intrasubtype superinfection

BackgroundThe potential role of antibodies in protection against intra-subtype HIV-1 superinfection remains to be understood. We compared the early neutralizing antibody (NAb) responses in three individuals, who were superinfected within one year of primary infection, to ten matched non-superinfected controls from a Zambian cohort of subtype C transmission cases. Sequence analysis of single genome amplified full-length envs from a previous study showed limited diversification in the individuals who became superinfected with the same HIV-1 subtype within year one post-seroconversion. We hypothesized that this reflected a blunted NAb response, which may have made these individuals more susceptible to superinfection.ResultsNeutralization assays showed that autologous plasma NAb responses to the earliest, and in some cases transmitted/founder, virus were delayed and had low to undetectable titers in all three superinfected individuals prior to superinfection. In contrast, NAbs with a median IC50 titer of 1896 were detected as early as three months post-seroconversion in non-superinfected controls. Early plasma NAbs in all subjects showed limited but variable levels of heterologous neutralization breadth. Superinfected individuals also exhibited a trend toward lower levels of gp120- and V1V2-specific IgG binding antibodies but higher gp120-specific plasma IgA binding antibodies.ConclusionsThese data suggest that the lack of development of IgG antibodies, as reflected in autologous NAbs as well as gp120 and V1V2 binding antibodies to the primary infection virus, combined with potentially competing, non-protective IgA antibodies, may increase susceptibility to superinfection in the context of settings where a single HIV-1 subtype predominates.

Intrasubtype C superinfected individuals mount delayed and low-titer autologous neutralizing antibody responses prior to superinfection

Background The potential role of neutralizing antibody in protecting against intra-subtype HIV-1 superinfection remains to be understood. We compared the early neutralizing antibody responses in three individuals, who were superinfected within one year of primary infection, to ten case-matched non-superinfected controls from a Zambian cohort of subtype C transmission cases. Sequence analysis of single genome amplified full-length env showed minimal diversification in the individuals who became superinfected with the same subtype of HIV-1 within year one postseroconversion. We hypothesized that these superinfected individuals had a muted neutralizing antibody response that elicited little pressure on the founder virus to escape. Methods We molecularly cloned envs from virus at the time of seroconversion and from virus at the time point that superinfection was detected. Using a TZM-BL pseudovirus reporter assay, we tested plasma neutralization of these autologous variants over the first year of infection. Results Neutralization assays showed that autologous plasma NAb titers to founder virus were low to undetectable in all three superinfected individuals prior to superinfection. In contrast, neutralizing antibodies with a median IC50 of 1:1896 were detected as early as three months postseroconversion in non-superinfected matched controls. There was no evidence, prior to superinfection, of crossneutralization of superinfecting variants in any of the three cases, although cross-neutralization breadth and potency to the subtype C pseudovirus reference panel was also limited in the plasma from non-superinfected individuals. Although there was a trend towards superinfected individuals having reduced levels of gp120 binding antibodies prior to superinfection compared to nonsuperinfected controls, this difference was not statistically significant between the groups. Conclusion These data suggest that development of antibodies, as reflected in autologous neutralizing antibodies to the primary infection variants, may provide protection and decrease susceptibility to superinfection.

Timing and source of subtype-C HIV-1 superinfection in the newly infected partner of Zambian couples with disparate viruses

BackgroundHIV-1 superinfection occurs at varying frequencies in different at risk populations. Though seroincidence is decreased, in the negative partner of HIV-discordant couples after joint testing and counseling in the Zambia Emory HIV Research Project (ZEHRP) cohort, the annual infection rate remains relatively high at 7-8%. Based on sequencing within the gp41 region of each partner's virus, 24% of new infections between 2004 and 2008 were the result of transmission from a non-spousal partner. Since these seroconvertors and their spouses have disparate epidemiologically-unlinked viruses, there is a risk of superinfection within the marriage. We have, therefore, investigated the incidence and viral origin of superinfection in these couples.ResultsSuperinfection was detected by heteroduplex mobility assay (HMA), degenerate base counting of the gp41 sequence, or by phylogenetic analysis of the longitudinal sequences. It was confirmed by full-length env single genome amplification and phylogenetic analysis. In 22 couples (44 individuals), followed for up to five years, three of the newly infected (initially HIV uninfected) partners became superinfected. In each case superinfection occurred during the first 12 months following initial infection of the negative partner, and in each case the superinfecting virus was derived from a non-spousal partner. In addition, one probable case of intra-couple HIV-1 superinfection was observed in a chronically infected partner at the time of his seroconverting spouse's initial viremia. Extensive recombination within the env gene was observed following superinfection.ConclusionsIn this subtype-C discordant couple cohort, superinfection, during the first year after HIV-1 infection of the previously negative partner, occurred at a rate similar to primary infection (13.6% [95% CI 5.2-34.8] vs 7.8% [7.1-8.6]). While limited intra-couple superinfection may in part reflect continued condom usage within couples, this and our lack of detecting newly superinfected individuals after one year of primary infection raise the possibility that immunological resistance to intra-subtype superinfection may develop over time in subtype C infected individuals.

Relevance of viral phenotype in the early AIDS outcome of pediatric HIV-1 primary infection.

In infants the clinical course of HIV-1 infection is bimodal, differing considerably from that of adults. The effect of HIV-1 phenotypic features and plasma viral load on the clinical course of infection has been well established in adults, whereas in children it remains controversial. The aim of this study was to prospectively evaluate the effect of HIV-1 replication phenotypes during the first year of primary infection in the development of premature immunosuppression and early pediatric AIDS. In 62 vertically infected children replication rates of HIV-1 isolates from primary cultures and syncytium-inducing capability in MT-2 cell line were evaluated, together with plasma viral load. It was observed that rapid replication rate and syncytium-inducing phenotype accelerate the early onset of pediatric AIDS (p = 0.02 and p = 0.04, respectively). Rapid replication kinetics was the only significantly independent variable for early clinical outcome (risk ratio, 2.48; p = 0.02). Both viral properties contributed to rapid CD4+ T-cell depletion (p = 0.05 for rapid replication rate, p = 0.01 for syncytium-inducing viral phenotype). Plasma viral burden higher than 5.5 log(10) copies/mL after 6 mo of age tended to be associated with disease progression. In conclusion, initial HIV-1 biologic features in pediatric primary infection by vertical transmission may influence the progression to early immunosuppression and development of AIDS.