Gaining CXCR4 utilization for HIV and SIV: Mechanisms and consequences.

Format:

Book

Thesis/Dissertation

Author/Creator:

Del Prete, Gregory Q.

Contributor:

University of Pennsylvania.

Language:

English

Subjects (All):

Virology.

Molecular biology.

0307.

0720.

Local Subjects:

0307.

0720.

Physical Description:

211 pages

Contained In:

Dissertation Abstracts International 71-01B.

System Details:

Mode of access: World Wide Web.

text file

Summary:

HIV-1 variants that use only the CCR5 coreceptor (R5 viruses) predominate early during in vivo infection, but viruses that use CXCR4 (X4 and R5X4 viruses) frequently emerge in AIDS patients in association with faster disease progression. Although the V3 loop has been identified as the principal determinant of coreceptor use, the functional mechanisms and consequences of coreceptor switching are poorly understood. In this thesis, we present two gain-of-function projects involving unique R5 viruses acquiring CXCR4 use.

Unlike HIV-1, SIVs rarely acquire CXCR4 utilization. Here, we first describe the derivation of 239-ST1.2-32, an R5X4 variant of SIVmac239. Two mutations in the 239-ST1.2-32 Env, K47E in Cl and L328W in V3, were required for CXCR4 use, suggesting that the determinants of SIV X4 tropism may be distinct from those for HIV-1. The acquisition of CXCR4 use was also associated with increased sensitivity to neutralization by SIVmac239+ sera/plasmas and by sCD4. Four rhesus macaques (RMs) were infected with 239-ST1.2-32 and we show that CXCR4 use is unfavorable for SIVmac239 in vivo. In two animals, 239-ST1.2-32 established high chronic viremia, reverted to strict R5 tropism, and restored sCD4 resistance in association with higher levels of env evolution and diversity, although K47E and L328W were maintained. In the other two animals, 239-ST1.2-32 replicated poorly during chronic infection, maintained X4 tropism and sCD4 sensitivity, and showed lower levels of env evolution and diversity in association with markers of superior immune responses.

In the second project, we derive two novel X4-tropic variants of the V3-truncated HIV-1 R3A DeltaV3(9,9) to evaluate the role of V3 and non-V3 domains in coreceptor switching. One X4 viruses, p11.20, acquired a positively-charged seven amino acid insertion in V3, which engendered interactions with the CXCR4 ECLs and rendered it sensitive to AMD3100 inhibition. Conversely, the other X4 virus, p7.10, maintained a fully truncated V3 and acquired the ability to interact with the CXCR4 NT, rendering it completely resistant to AMD3100. These findings demonstrate HIV-1 that coreceptor switching can involve V3 loop changes that allow interactions with the CXCR4 ECLs, or it can alternatively involve mutations that allow gp120 interactions with the CXCR4 NT.

Notes:

Source: Dissertation Abstracts International, Volume: 71-01, Section: B, page: 0151.

Adviser: James A. Hoxie.

Thesis (Ph.D.)--University of Pennsylvania, 2009.

Local Notes:

School code: 0175.

ISBN:

9781109581850

Access Restriction:

Restricted for use by site license.