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Host Genetic Influences on Highly Active Antiretroviral Therapy Efficacy and AIDS-Free Survival

Hendrickson, Sher L PhD*; Jacobson, Lisa P MS, ScD; Nelson, George W PhD; Phair, John P MD§; Lautenberger, James PhD*; Johnson, Randall C MPH; Kingsley, Lawrence DrPH; Margolick, Joseph B MD, PhD; Detels, Roger MS, MD#; Goedert, James J MD**; O'Brien, Stephen J PhD*

JAIDS Journal of Acquired Immune Deficiency Syndromes: July 1st, 2008 - Volume 48 - Issue 3 - p 263-271
doi: 10.1097/QAI.0b013e31816fdc5f
Basic Science

We studied the influence of AIDS restriction genes (ARGs) CCR5-Δ32, CCR2-64I, SDF1-3A, IL10-5′A, CX3CR1-V249I, CX3CR1-T280M, and MDR1-C3435T and haplotypes of the CCR5 P1 promoter and RANTES variants −403A, In1.1C, 3222C, and −28G among HIV-1 infected patients on highly active antiretroviral therapy (HAART) in the Multicenter AIDS Cohort Study (MACS) and the Multicenter Hemophilia Cohort Study (MHCS). Our results indicate that several ARGs also influence therapy efficacy (ie, the success in viral suppression) and subsequent progression to AIDS while on HAART. CCR5-Δ32 decreased time to viral suppression (<200 HIV RNA copies/mL, relative hazard [RH] = 1.40; P = 0.008) and was protective against AIDS (RH = 0.11; P = <0.0001), whereas the CCR5 P1 haplotype was associated with delayed viral suppression (RNA <50 copies/mL, odds ratio [OR] = 0.65; P = 0.03) and accelerated time to AIDS (RH = 2.68; P = 0.02). SDF1-3A reduced viral suppression (OR = 0.61; P = 0.02) and accelerated AIDS (RH = 3.18; P = 0.009). Accelerated AIDS progression was also observed with the RANTES haplotype carrying RANTES-IN1.1C and RANTES-3222C (P = 0.005 to 0.007). In contrast, the RANTES haplotype H1, which lacks suspected deleterious single-nucleotide polymorphisms, was protective against AIDS. CX3CR1-V249I seemed to accelerate viral suppression (RNA <50 copies/mL, OR = 1.27; P = 0.01). ARG influence after HAART suggests residual HIV-1 replication, and spread continues even in patients successfully suppressing detectable viral RNA.

From the *Laboratory of Genomic Diversity, National Cancer Institute, Frederick, MD; †Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD; ‡Laboratory of Genomic Diversity, Science Applications International Corporation--Frederick, Inc., National Cancer Institute-Frederick, Frederick, MD; §Division of Infectious Diseases, Feinberg School of Medicine, Northwestern University, Chicago, IL; ∥Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, PA; ¶Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; #University of California, UCLA Schools of Public Health and Medicine, Los Angeles, CA; and the **Viral Epidemiology Branch, National Cancer Institute, Rockville, MD.

Received for publication August 31, 2007; accepted February 21, 2008.

Supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. The Multicenter AIDS Cohort Study is funded by the National Institute of Allergy and Infectious Diseases, with additional supplemental funding from the National Cancer Institute. National Cancer Institute contracts include: UO1-AI-35042, 5-MO1-RR-00722 (General Clinical Research Centers), UO1-AI-35043, UO1-AI-37984, UO1-AI-35039, UO1-AI-35040, UO1-AI-37613, UO1-AI-35041, and N01-CO-12400.

None of the authors in this manuscript have commercial or other associations that pose a conflict of interest. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.

Correspondence to: Sher Hendrickson, PhD, National Cancer Institute, Frederick, MD 21702-1201 (e-mail: hendricksons@mail.nih.gov) or Stephen J. O'Brien, PhD, Chief, Laboratory of Genomic Diversity, National Cancer Institute, Frederick, MD 21702-1201 (e-mail: obrien@ncifcrf.gov).

© 2008 Lippincott Williams & Wilkins, Inc.