Relative resistance of HIV-1 founder viruses to control by interferon-alpha

被引：166

作者：

Fenton-May, Angharad E. ^{[1
]}

Dibben, Oliver ^{[1
]}

Emmerich, Tanja ^{[1
]}

Ding, Haitao ^{[2
]}

Pfafferott, Katja ^{[1
]}

Aasa-Chapman, Marlen M. ^{[3
,4
]}

Pellegrino, Pierre ^{[5
]}

Williams, Ian ^{[5
]}

Cohen, Myron S. ^{[6
]}

Gao, Feng ^{[7
,8
]}

Shaw, George M. ^{[9
,10
]}

Hahn, Beatrice H. ^{[9
,10
]}

Ochsenbauer, Christina ^{[2
]}

Kappes, John C. ^{[2
,11
]}

Borrow, Persephone ^{[1
]}

机构：

[1] Univ Oxford, Nuffield Dept Med, Oxford OX3 7FZ, England

[2] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA

[3] Fac Med, Div Infect & Immun, London, England

[4] Ctr Sexual Hlth & HIV Res, London, England

[5] UCL, Mortimer Market Ctr, Ctr Sexual Hlth & HIV Res, London, England

[6] Univ N Carolina, Dept Med, Chapel Hill, NC USA

[7] Duke Univ, Med Ctr, Duke Human Vaccine Inst, Durham, NC USA

[8] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA

[9] Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA

[10] Univ Penn, Dept Microbiol, Perelman Sch Med, Philadelphia, PA 19104 USA

[11] Birmingham Vet Affairs Med Ctr, Res Serv, Birmingham, AL USA

来源：

RETROVIROLOGY | 2013年 / 10卷

关键词：

Human immunodeficiency virus type 1; Type; 1; interferon; Viral inhibition; Founder virus; Acute infection; SIMIAN IMMUNODEFICIENCY VIRUS; PERSISTENT LCMV INFECTION; I INTERFERON; GENE-EXPRESSION; REPLICATION CAPACITY; T-CELLS; MUCOSAL TRANSMISSION; REGULATORY FACTOR-3; DISEASE PROGRESSION; VIRAL REPLICATION;

D O I：

10.1186/1742-4690-10-146

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

摘要：

Background: Following mucosal human immunodeficiency virus type 1 (HIV-1) transmission, type 1 interferons (IFNs) are rapidly induced at sites of initial virus replication in the mucosa and draining lymph nodes. However, the role played by IFN-stimulated antiviral activity in restricting HIV-1 replication during the initial stages of infection is not clear. We hypothesized that if type 1 IFNs exert selective pressure on HIV-1 replication in the earliest stages of infection, the founder viruses that succeed in establishing systemic infection would be more IFN-resistant than viruses replicating during chronic infection, when type 1 IFNs are produced at much lower levels. To address this hypothesis, the relative resistance of virus isolates derived from HIV-1-infected individuals during acute and chronic infection to control by type 1 IFNs was analysed. Results: The replication of plasma virus isolates generated from subjects acutely infected with HIV-1 and molecularly cloned founder HIV-1 strains could be reduced but not fully suppressed by type 1 IFNs in vitro. The mean IC50 value for IFNa2 (22 U/ml) was lower than that for IFN beta (346 U/ml), although at maximally-inhibitory concentrations both IFN subtypes inhibited virus replication to similar extents. Individual virus isolates exhibited differential susceptibility to inhibition by IFNa2 and IFN beta, likely reflecting variation in resistance to differentially up-regulated IFN-stimulated genes. Virus isolates from subjects acutely infected with HIV-1 were significantly more resistant to in vitro control by IFNa than virus isolates generated from the same individuals during chronic, asymptomatic infection. Viral IFN resistance declined rapidly after the acute phase of infection: in five subjects, viruses derived from six-month consensus molecular clones were significantly more sensitive to the antiviral effects of IFNs than the corresponding founder viruses. Conclusions: The establishment of systemic HIV-1 infection by relatively IFNa-resistant founder viruses lends strong support to the hypothesis that IFNa plays an important role in the control of HIV-1 replication during the earliest stages of infection, prior to systemic viral spread. These findings suggest that it may be possible to harness the antiviral activity of type 1 IFNs in prophylactic and potentially also therapeutic strategies to combat HIV-1 infection.

引用

页数：18

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