Unique phenotypic characteristics of recently transmitted HIV-1 subtype C envelope glycoprotein gp120: Use of CXCR6 co-receptor by transmitted founder viruses.

Ashokkumar, M.; Aralaguppe, S.G.; Tripathy, S.P.; Hanna, L.E.; Neogi, U.

Journal of Virology; 2018; 92(9).

Abstract: Adequate information on the precise molecular and biological composition of the viral strains that establish HIV infection in the human host will provide effect 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-Nef?gp120 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 analysed for molecular features of the envelope, per-infectious-particle infectivity, co-receptor 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 co-receptor usage, in addition to that of the CCR5 co-receptor, 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 PG121) was found to be much lower than that of the virus variants from the adults in the chronic stage of infection.

Importance: Tremendous progress has been made 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 acquihired infection from the mother and have come up with unique characterizations for the TYF virus that establishes infection in the human host.

Keywords: Transmitted founder virus; amino acid diversity; co-receptor tropism; human immunodeficiency virus; mother-to-child transmission; resistance to neutralization,

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