Unique Phenotypic Characteristics of Recently Transmitted HIV-1 Subtype C Envelope Glycoprotein gp120: Use of CXCR6 Coreceptor by Transmitted Founder Viruses

Abstract

Adequate information on the precise molecular and biological composition of the viral strains that establish HIV infection in the human host will provide effective means of immunization against HIV infection. In an attempt to identify the transmitted founder (TF) virus and differentiate the biological properties and infectious potential of the TF virus from those of the population of the early transmitted viruses, 250 patient-derived gp120 envelope glycoproteins were cloned in pMN-K7-Luc-IRESs-NefΔgp120 to obtain chimeric viruses. Samples were obtained from eight infants who had recently become infected with HIV through mother-to-child transmission (MTCT) and two adults who acquired infection through the heterosexual route and were in the chronic stage of infection. Among the 250 clones tested, 65 chimeric viruses were infectious, and all belonged to HIV-1 subtype C. The 65 clones were analyzed for molecular features of the envelope, per-infectious-particle infectivity, coreceptor tropism, drug sensitivity, and sensitivity to broadly neutralizing antibodies. Based on genotypic and phenotypic analysis of the viral clones, we identified 10 TF viruses from the eight infants. The TF viruses were characterized by shorter V1V2 regions, a reduced number of potential N-linked glycosylation sites, and a higher infectivity titer compared to the virus variants from the adults in the chronic stage of infection. CXCR6 coreceptor usage, in addition to that of the CCR5 coreceptor, which was used by all 65 chimeric viruses, was identified in 13 viruses. The sensitivity of the TF variants to maraviroc and a standard panel of neutralizing monoclonal antibodies (VRC01, PG09, PG16, and PGT121) was found to be much lower than that of the virus variants from the adults in the chronic stage of infection. Tremendous progress has been made during the last three and half decades of HIV research, but some significant gaps continue to exist. One of the frontier areas of HIV research which has not seen a breakthrough yet is vaccine research, which is because of the enormous genetic diversity of HIV-1 and the unique infectious fitness of the virus. Among the repertoire of viral variants, the virus that establishes successful infection (transmitted founder [TF] virus) has not been well characterized yet. An insight into the salient features of the TF virus would go a long way toward helping with the design of an effective vaccine against HIV. Here we studied the biological properties of recently transmitted viruses isolated from infants who acquired infection from the mother and have come up with unique characterizations for the TF virus that establishes infection in the human host.

In vitro replicative fitness of early Transmitted founder HIV-1 variants and sensitivity to Interferon alpha

“…Non-TF viruses have longer variable regions, greater number of PNGs and show increased sensitivity to neutralizing antibodies. The phenotypic differences between the two virus types described in this article have been reported earlier by our group 28 .…”

“…In this study, we generated several infectious chimeric virus clones from eight HIV-infected infants during the very early stages of infection and classified them as TF and NT viruses based on their genetic and phenotypic properties. TF viruses had short variable regions with a fewer number of glycosylation sites in their envelope and possessed unique phenotypic properties such as higher infectivity titer, differential co-receptor usage, reduced sensitivity to neutralizing antibodies and the co-receptor antagonist, MVC, as reported in one of our earlier studies 28 . NT viruses failed to exhibit any of the characteristics mentioned above.…”

“…To summarize, there are very limited studies that have characterized in detail the differential co-receptor usage 7 , replicative fitness 25 , interferon resistance 20,25,30 and viral productivity 26 of TF and NT viruses within an individual or between linked transmission pairs. In a previous study, we demonstrated differential co-receptor usage of TF viruses 28 . For the very first time, we have reported on the interferon resistance and fitness of TF and NT viruses within an individual here.…”

“…This study has a limitation that needs to be mentioned. As described previously 28 , the backbone used for cloning gp120 region of HIV-1 was that of subtype B. The viruses produced from these clones were recombinants of both subtype C and B.…”

“…Studies have shown that the viral variants in the transmitting partner were different from the transmitted founder virus in the newly infected partner 25 . In this study, we identified TF and NT variants by comparing the genetic identity between the different infectious clones generated from the same individual 28 as well as the HIV-1 env DNA isolated from peripheral blood mononuclear cells (PBMC) 29 of the infant. TF viruses and the provirus in the PBMCs are reported to have a very close genetic signature (shorter variable regions and fewer PNGs).…”