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

ABSTRACT: Type I interferons, particularly interferon-alpha (IFN-?), play a vital role in the host's anti-viral defenses by interfering with viral replication. However, the virus rapidly evolves to exploit the IFN-? response for its replication, spread, and pathogenic function. In this study, we attempted to determine IFN-? susceptibility and productivity of infectious transmitted/founder (TF) (n?=?8) and non-transmitted (NT) viruses (n?=?8) derived from HIV-1 infected infants. Independent experiments were carried out to determine IFN-? resistance, replication fitness, and viral productivity in CD4+ T cells over a short period. In vitro studies showed that TF viruses were resistant to IFN-? during the very near moment of transmission, but in the subsequent time points, they became susceptible to IFN-?. We did not observe much difference in replicative fitness of the TF viruses in cultures treated with and without IFN-?, but the difference was significant in the case of NT viruses obtained from the same individual. Despite increased susceptibility to IFN-?, NT viruses produced more viral particles than TF viruses. Similar results were also obtained in cultures treated with maraviroc (MVC). The study identified unique characteristics of TF viruses thus prompting further investigation into virus-host interaction occurring during the early stages of HIV infection.

SUBMITTER: Ashokkumar M

PROVIDER: S-EPMC7026412 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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

Ashokkumar Manickam M Sonawane Aanand A Sperk Maike M Tripathy Srikanth P SP Neogi Ujjwal U Hanna Luke Elizabeth LE

Scientific reports 20200217 1

Type I interferons, particularly interferon-alpha (IFN-α), play a vital role in the host's anti-viral defenses by interfering with viral replication. However, the virus rapidly evolves to exploit the IFN-α response for its replication, spread, and pathogenic function. In this study, we attempted to determine IFN-α susceptibility and productivity of infectious transmitted/founder (TF) (n = 8) and non-transmitted (NT) viruses (n = 8) derived from HIV-1 infected infants. Independent experiments wer ...[more]

PMID: 32066770

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Project description:Human immunodeficiency virus type 1 (HIV-1) infection often arises from a single transmitted/founder (TF) viral variant among a large pool of viruses in the quasispecies in the transmitting partner. TF variants are typically nondominant in blood and genital secretions, indicating that they have unique traits. The plasmacytoid dendritic cell (pDC) is the primary alpha interferon (IFN-?)-producing cell in response to viral infections and is rapidly recruited to the female genital tract upon exposure to HIV-1. The impact of pDCs on transmission is unknown. We investigated whether evasion of pDC responses is a trait of TF viruses. pDCs from healthy donors were stimulated in vitro with a panel of 20 HIV-1 variants, consisting of one TF variant and three nontransmitted (NT) variants each from five transmission-linked donor pairs, and secretion of IFN-? and tumor necrosis factor alpha (TNF-?) was measured by enzyme-linked immunosorbent assay (ELISA). No significant differences in cytokine secretion in response to TF and NT viruses were observed, despite a trend toward enhanced IFN-? and TNF-? production in response to TF viruses. NT viruses demonstrated polarization toward production of either IFN-? or TNF-?, indicating possible dysregulation. Also, for NT viruses, IFN-? secretion was associated with increased resistance of the virus to inactivation by IFN-? in vitro, suggesting in vivo evolution. Thus, TF viruses do not appear to preferentially subvert pDC activation compared to that with nontransmitted HIV-1 variants. pDCs may, however, contribute to the in vivo evolution of HIV-1.IMPORTANCE The plasmacytoid dendritic cell (pDC) is the first cell type recruited to the site of HIV-1 exposure; however, its contribution to the viral bottleneck in HIV-1 transmission has not been explored previously. We hypothesized that transmitted/founder viruses are able to avoid the pDC response. In this study, we used previously established donor pair-linked transmitted/founder and nontransmitted (or chronic) variants of HIV-1 to stimulate pDCs. Transmitted/founder HIV-1, instead of suppressing pDC responses, induced IFN-? and TNF-? secretion to levels comparable to those induced by viruses from the transmitting partner. We noted several unique traits of chronic viruses, including polarization between IFN-? and TNF-? production as well as a strong relationship between IFN-? secretion and the resistance of the virus to neutralization. These data rule out the possibility that TF viruses preferentially suppress pDCs in comparison to the pDC response to nontransmitted HIV variants. pDCs may, however, be important drivers of viral evolution in vivo.

Dataset Information

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

Publications

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

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