A remarkable genetic shift in a transmitted/founder virus broadens antibody responses against HIV-1.

Autor:	Jain S; Bacteriophage Medical Research Center, Department of Biology, The Catholic University of America, Washington, United States., Uritskiy G; Bacteriophage Medical Research Center, Department of Biology, The Catholic University of America, Washington, United States., Mahalingam M; Bacteriophage Medical Research Center, Department of Biology, The Catholic University of America, Washington, United States., Batra H; Bacteriophage Medical Research Center, Department of Biology, The Catholic University of America, Washington, United States., Chand S; Bacteriophage Medical Research Center, Department of Biology, The Catholic University of America, Washington, United States., Trinh HV; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, United States.; Laboratory of Adjuvant and Antigen Research, U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, United States., Beck C; Department of Molecular Genetics and Microbiology, Duke University, Durham, United States., Shin WH; Department of Biological Sciences, Purdue University, West Lafayette, United States.; Department of Chemistry Education, Sunchon National University, Suncheon, Republic of Korea.; Department of Advanced Components and Materials Engineering, Sunchon National University, Suncheon, Republic of Korea., Alsalmi W; Bacteriophage Medical Research Center, Department of Biology, The Catholic University of America, Washington, United States., Kijak G; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, United States.; Laboratory of Adjuvant and Antigen Research, U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, United States., Eller LA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, United States., Kim J; Laboratory of Adjuvant and Antigen Research, U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, United States., Kihara D; Department of Biological Sciences, Purdue University, West Lafayette, United States.; Department of Computer Science, Purdue University, West Lafayette, United States., Tovanabutra S; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, United States.; Laboratory of Adjuvant and Antigen Research, U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, United States., Ferrari G; Department of Molecular Genetics and Microbiology, Duke University, Durham, United States., Robb ML; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, United States., Rao M; Laboratory of Adjuvant and Antigen Research, U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, United States., Rao VB; Bacteriophage Medical Research Center, Department of Biology, The Catholic University of America, Washington, United States.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2024 Apr 15; Vol. 13. Date of Electronic Publication: 2024 Apr 15.
DOI:	10.7554/eLife.92379
Abstrakt:	A productive HIV-1 infection in humans is often established by transmission and propagation of a single transmitted/founder (T/F) virus, which then evolves into a complex mixture of variants during the lifetime of infection. An effective HIV-1 vaccine should elicit broad immune responses in order to block the entry of diverse T/F viruses. Currently, no such vaccine exists. An in-depth study of escape variants emerging under host immune pressure during very early stages of infection might provide insights into such a HIV-1 vaccine design. Here, in a rare longitudinal study involving HIV-1 infected individuals just days after infection in the absence of antiretroviral therapy, we discovered a remarkable genetic shift that resulted in near complete disappearance of the original T/F virus and appearance of a variant with H173Y mutation in the variable V2 domain of the HIV-1 envelope protein. This coincided with the disappearance of the first wave of strictly H173-specific antibodies and emergence of a second wave of Y173-specific antibodies with increased breadth. Structural analyses indicated conformational dynamism of the envelope protein which likely allowed selection of escape variants with a conformational switch in the V2 domain from an α-helix (H173) to a β-strand (Y173) and induction of broadly reactive antibody responses. This differential breadth due to a single mutational change was also recapitulated in a mouse model. Rationally designed combinatorial libraries containing 54 conformational variants of V2 domain around position 173 further demonstrated increased breadth of antibody responses elicited to diverse HIV-1 envelope proteins. These results offer new insights into designing broadly effective HIV-1 vaccines. Competing Interests: SJ, GU, MM, HB, SC, HT, CB, WS, WA, LE, JK, DK, ST, GF, MR, MR, VR No competing interests declared, GK Gustavo Kijak is affiliated with AstraZeneca and owns stocks/shares. The author has no other competing interests to declare
Databáze:	MEDLINE
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