Abstract

The basis for the extensive variability seen in the reconstitution of CD4⁺ T cell counts in HIV-infected individuals receiving highly active antiretroviral therapy (HAART) is not fully known. Here, we show that variations in CCL3L1 gene dose and CCR5 genotype, but not major histocompatibility complex HLA alleles, influence immune reconstitution, especially when HAART is initiated at <350 CD4⁺ T cells/mm³. The CCL3L1-CCR5 genotypes favoring CD4⁺ T cell recovery are similar to those that blunted CD4⁺ T cell depletion during the time before HAART became available (pre-HAART era), suggesting that a common CCL3L1-CCR5 genetic pathway regulates the balance between pathogenic and reparative processes from early in the disease course. Hence, CCL3L1-CCR5 variations influence HIV pathogenesis even in the presence of HAART and, therefore, may prospectively identify subjects in whom earlier initiation of therapy is more likely to mitigate immunologic failure despite viral suppression by HAART. Furthermore, as reconstitution of CD4⁺ cells during HAART is more sensitive to CCL3L1 dose than to CCR5 genotypes, CCL3L1 analogs might be efficacious in supporting immunological reconstitution.

1. Veterans Administration Research Center for AIDS and HIV-1 Infection, South Texas Veterans Health Care System, 7400 Merton Minter, San Antonio, Texas 78229, USA.
2. Department of Medicine, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, Texas 78229, USA.
3. Departments of Microbiology and Immunology and Biochemistry, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, Texas 78229, USA.
4. Infectious Disease Clinical Research Program, Uniformed Services University, 4301 Jones Bridge Road, Bethesda, Maryland 20814, USA.
5. Infectious Diseases Service, Wilford Hall United States Air Force Medical Center, 2200 Bergquist Drive, Lackland Air Force Base, Texas 78236, USA.
6. Henry M. Jackson Foundation, Wilford Hall United States Air Force Medical Center, 2200 Bergquist Drive, Lackland Air Force Base, Texas 78236, USA.
7. San Antonio Military Medical Center, 3851 Roger Brooke Drive, Fort Sam Houston, Texas 78234, USA.
8. University of North Carolina, 4030 Bondurant Hall, Chapel Hill, North Carolina 27599, USA.
9. Antiviral Research Center, Department of Medicine, University of California, 150 West Washington Street, San Diego, California 92103, USA.
10. Veterans Affairs San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, California 92161, USA.
11. Department of Epidemiology and Biostatistics, University of California, 185 Berry Street, San Francisco, California 94107, USA.
12. Department of Medicine, San Francisco General Hospital, University of California–San Francisco, 995 Potrero Avenue, San Francisco, California 94110, USA.
13. These authors contributed equally to this work.

Correspondence to: Sunil K Ahuja^1,2,3 e-mail: ahujas@uthscsa.edu

Correspondence to: Matthew J Dolan^4,5,6,7 e-mail: mdolan@hjf.org

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