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Host Determinants in HIV Infection and Disease: Part 2: Genetic Factors and Implications for Antiretroviral Therapeutics*

Christine M. Hogan, MD; and Scott M. Hammer, MD
[+] Article and Author Information

From Columbia University College of Physicians and Surgeons, New York, New York.


Part 1 of this review was published in the 1 May 2001 issue.

Acknowledgment: The authors thank Brian-Fred Fitzsimmons, MD, for assistance with preparation of the figures.

Grant Support: Dr. Hammer is supported by grants AI46386 and AI48013 from the National Institute of Allergy and Infectious Diseases. Dr. Hogan is supported in part by Center for AIDS Research grant 5P30AI42848-03 from the National Institute of Health and the National Institute of Allergy and Infectious Diseases and in part by the SmithKline Beecham Development Partners Junior Faculty Award.

Requests for Single Reprints: Christine M. Hogan, MD, Division of Infectious Diseases, Columbia University, College of Physicians and Surgeons, P & S Box 82, 630 West 168th Street, New York, NY 10032; e-mail, ch358@columbia.edu.

Current Author Addresses: Drs. Hogan and Hammer: Division of Infectious Diseases, Columbia University, College of Physicians and Surgeons, P & S Box 82, 630 West 168th Street, New York, NY 10032.


Ann Intern Med. 2001;134(10):978-996. doi:10.7326/0003-4819-134-10-200105150-00012
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The course of HIV infection varies widely among individuals. Immunologic and genetic studies of long-term nonprogressors and exposed yet uninfected persons have helped to elucidate the mechanisms by which some persons are protected from HIV acquisition or have slow rates of disease progression. This two-part review describes what is currently known about host factors in HIV-1 infection. Studies for inclusion were identified by a systematic search of PubMed for English-language literature published from 1988 through June 2000. Abstracts of presentations at major meetings convened in 2000 were also included if appropriate. The first part of the review discussed cellular and humoral immunity to HIV infection. This second part describes genetic host factors—namely, inheritance of mutant chemokine receptors or ligands, such as CCR5-Δ32, CCR2-V64I, stromal cell–derived factor-1 3′α, and CCR5 promoter polymorphisms, as well as HLA type—that affect susceptibility to infection and subsequent clinical course. Soluble inhibitory factors, the cytokine milieu, and concomitant infections also affect outcome. Knowledge of host responses is increasingly being applied to new therapeutic strategies, including early treatment, immune modulation, structured treatment interruptions, therapeutic vaccination, and new chemotherapeutic agents, as well as to vaccine development.

Figures

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Figure 1.
Schematic overview of host responses at the cellular, local, and systemic levels.+CTLs+R5X4MIPSDFIFNILTNF

At the cellular level, CD8 cytotoxic T cells ( ), with the help of CD4 T-helper cells, lyse HIV-infected cells (discussed in part 1 of the review). Soluble factors and neutralizing antibodies inhibit viral replication. Macrophage-tropic HIV ( ) infects cells bearing CD4 and CCR5 co-receptor. T-cell–tropic HIV ( ) infects cells bearing CD4 and CXCR4 co-receptor. RANTES (regulated on activation, normal T expressed and secreted); macrophage inflammatory protein ( )-1α; and MIP-1β—natural ligands for the CCR5 receptor—block R5 from infecting CCR5-bearing cells. Stromal cell–derived factor ( )-1, the natural ligand for the CXCR4 receptor, may block X4 from infecting CXCR4-bearing cells. Macrophages from persons bearing the CCR5-Δ32 mutation and thus lacking the CCR5 co-receptor are not infected by macrophage-tropic HIV (R5). At the local level, mucosal CTLs and mucosal IgA may inhibit initial viral replication (discussed in part 1). Concomitant infections activate T cells, providing target cells for HIV to infect. Systemically, such inhibiting factors as CTLs, antibodies, interferon ( ), and interleukin ( )-16 are countered with such stimulating factors as tumor necrosis factor ( ), IL-1, IL-6, and co-infections. Interleukin-10 inhibits IL-6 and TNF-α. The rectangular bars indicate sites of blockade. STD = sexually transmitted disease.

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Figure 2.
Interaction of HIV with its coreceptors.M-tropicR5RANTESMIPT-tropicX4SDF-1

The interaction between the virus envelope protein gp120 and CD4 induces a conformational change that allows interaction between the virus and the chemokine receptor and ultimate fusion of the virus and the host cell membrane. Macrophage-tropic ( or ) HIV infects cells bearing CD4 and the CCR5 chemokine receptor. This interaction is blocked by natural ligands for CCR5: (regulated on activation, normal T expressed and secreted); macrophage inflammatory protein ( )-1α; and MIP-1β. T-cell-tropic ( or ) HIV infects cells bearing CD4 and the CXCR4 chemokine receptor. This interaction may be blocked by stromal cell–derived factor-1 ( ), the natural ligand for CXCR4.

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