DOSSIER Web site: http://statepi.jhsph.edu/macs/macs.html Prepared by CAMACS Fax: 410-955-7587 May 2011 The MACS is funded by the National Institute of Allergy and Infectious Diseases, with additional supplemental funding from the National Cancer Institute and the National Heart, Lung and Blood Institute. UO1-AI-35042, UL1-RR025005, UO1-AI-35043, UO1-AI- 35039, UO1-AI-35040, UO1-AI-35041.
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DOSSIER
Web site: http://statepi.jhsph.edu/macs/macs.htmlPrepared by CAMACS
Fax: 410-955-7587
May 2011
The MACS is funded by the National Institute of Allergy and Infectious Diseases, with additional supplemental funding from the National Cancer Institute and the National Heart, Lung and Blood Institute. UO1-AI-35042, UL1-RR025005, UO1-AI-35043, UO1-AI-35039, UO1-AI-35040, UO1-AI-35041.
Imagawa DT, et al. Human immunodeficiency virus type 1 infection in homosexual men who remain seronegative for prolonged periods. N Engl J Med 1989; 320(22):1458-1462.
Results: Median percentage of CD25+/CD8+ activated cells higher in resistant men
Genetic Study
23 resistant men137 low-risk seroconverters
Results: Significantly higher levels of TAP 1.4 and TAP 1.4/2.3 genes in resistant men
Interpretation: Genetic factors (MHC transport?) are associated with resistance to infection
Detels R, et al. Persistently seronegative men from whom HIV-1 has been isolated are genetically and immunologically distinct. Immunol Lett 1996; 51:29-33.
CCR5 Confers Protection
Methods/Results:
111 resistant, 4.5% CCR5 homozygous
614 seropositive, 0% CCR5 homozygous
Interpretation: 100% absence of CCR5 receptor on CD4 cells confers 100% protection
Zimmerman PA, et al. Inherited resistance to HIV-1 conferred by an inactivating mutation in CC chemokine receptor 5: studies in populations with contrasting clinical phenotypes, defined racial background, and quantified risk. Mol Med 1997; 3(1):23-36.
AIDS-Free Time by Calendar
May 2000
Detels, Muñoz, . . ., Phair - JAMA 1998 (update)
Years since Seroconversion0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
0
10
20
30
40
50
60
70
80
90
100
Calendar
86.0 to 89.5 341 36 1.48 (0.119)89.5 to 93.0 427 91 1 - 1 -
93.0 to 96.5 378 100 0.92 (0.626) 1.03 (0.690)
96.5 to 99.5 264 20 0.30 (<.001) 2.11 (<.001)
N AIDS RH (p-value) RT (p-value)
Per
cen
t A
IDS
-Fre
e
Interpretation: HAART delays onset of AIDS
Effect of HLA-B Alleles on AIDS Progression (N=1,089)
A. Replication cohort (ALIVE, MACS, MHCS, SFCC, individuals genotyped by Steve O’BrienB. Combined analysis of replication and discovery cohorts (156 MACS individuals enriched with
rapid progressors and long-term non-progressors
Herbeck, Gottlieb, … Mullins. J Infect Dis 2010
May 2010
Kaplan-Meier Survival Curves for Genotypes of SNP rs17762192, Representing a Haplotype Located 36kb Upstream of PROX1 and
Chromosome 1, Showing Strong Associations with Differing Rates of Progression to Clinical AIDS
Time to AIDS Following HAART According to Selected Genotypings