HIV-1 Subtype as a Determinant of Disease Progression

Although the average time from infection with HIV type 1 (HIV-1) to the development of AIDS is 1 decade, the rate of disease progression varies considerably among infected persons. Numerous factors, including plasma HIV-1 RNA level, CD4 cell count, degree of immune activation, age, socioeconomic status, and host genetics, contribute to determining the rate of progression in the individual patient [1]. Intrinsic viral properties, such as coreceptor use and replication capacity, may also influence progression rates. Data have been accumulating to suggest that viral subtype is another contributing factor [2– 4]. The report by Kiwanuka et al. [5] in this issue of the journal provides compelling evidence that infection with HIV-1 subtype A (HIV-1A) progresses more slowly than infection with HIV-1 subtype D (HIV-1D) or with recombinant or multiple HIV-1 subtypes. As summarized in the report by Kiwanuka and colleagues, HIV is classified into types (HIV-1 or HIV type 2), groups (HIV-1 M, N, and O), and subtypes (or clades) on the basis of genetic relatedness. At present, 9 subtypes are recognized (A–D, F–H, J, and K), along with several circulating recombinant forms, which contain sequences from 1 subtype. Because the different HIV-1 subtypes are not uniformly dispersed, comparisons of virulence and transmissibility are hampered by potential confounders, such as ethnic, socioeconomic, and other epidemiological factors. The cocirculation of HIV-1A, HIV-1D, and several intersubtype recombinants in the Rakai district of Uganda provides an opportunity to compare rates of disease progression associated with these different subtypes within a similar population. In the current report, Kiwanuka et al. [5] compared rates of progression among HIV-1 seroconverters who were followed as part of the Rakai Health Sciences Program. Subjects identified during 1997–2002 were followed through 2004, when antiretroviral therapy became available in Rakai district. The HIV-1 subtype was determined by a multiregion hybridization assay in which gag, pol, vpu, env, and gp41 amplicons from polymerase chain reaction (PCR) of plasma HIV-1 RNA were tested in a second-round PCR with subtype-specific Taqman probes. This approach allowed the authors to categorize samples as comprising a single subtype, mixtures of 2 subtypes, or intersubtype recombinants. The primary end point was the time to achievement of a CD4 cell count of 250 cells/mm3 or death due to AIDS. Of the 350 seroconverters enrolled, nearly 60% were infected with HIV-1D, 15% with HIV-1A, 21% with recombinant subtypes, and 4% with multiple subtypes. Progression to a CD4 cell count of 250 cells/mm3 was significantly less common among subjects infected with HIV-1A (20%), compared with subjects infected with HIV-1D (40%), recombinant forms (40%), or multiple subtypes (53%) (P .03). Death from AIDS was also less common among subjects infected with HIV-1A. These differences were reflected in the longer time to AIDS onset for HIV-1A–infected subjects (8.05 years), compared with those infected with HIV-1D (6.49 years), recombinant forms (5.57 years), or multiple subtypes (5.80 years). In multivariable models that controlled for virus load, age, and sex, subjects infected with multiple subtypes, HIV-1D, or intersubtype recombinants were 4.40, 2.13, and 2.16 times, respectively, more likely to progress to AIDS, compared with those infected with HIV1A. Similarly, subjects infected with non-A subtypes had an approximately 6 – 8-fold greater risk of death from AIDS. Previous studies involving cohorts of persons with seroprevalent infection also found that the risk of disease progression is greater for persons with HIV-1D infection than for those with HIV-1A infection [3, 4]. Although seroprevalent cohorts can provide important information about late events, such as death after AIDS, they potentially suffer from survival bias (i.e., subjects with rapid progression tend to be Received 26 November 2007; accepted 26 November 2007; electronically published 11 February 2008. Potential conflicts of interest: none reported. Financial support: National Institutes of Health (grants R37 AI-055357 and K24 RR016482). Reprints or correspondence: Dr. Daniel R. Kuritzkes, Sect. of Retroviral Therapeutics, Brigham and Women’s Hospital, 65 Landsdowne St., Rm. 449, Cambridge, MA 02139 (dkuritzkes@partners.org). The Journal of Infectious Diseases 2008; 197:638 –9 © 2008 by the Infectious Diseases Society of America. All rights reserved. 0022-1899/2008/19705-0002$15.00 DOI: 10.1086/527417 E D I T O R I A L C O M M E N T A R Y