Significance of HIV-1 genetic subtypes

Abstract

The human immunodeficiency virus type 1 (HIV-1) displays high genetic variability. Phylogenetic studies have shown that a majority of HIV-1 sequences cluster into one large group called M (major), whereas a few are clearly distinct, group O (outlier) and group N (non-M-non-O). Group M sequences are further subdivided into at least nine genetic subtypes, A through H and J. Inter-subtype recombinants also exist. The geographical distribution of different subtypes varies. Subtype B dominates in Europe and North America. All subtypes have been described in Africa, but subtypes A, C and D dominates. Subtype C is probably the most prevalent subtype world-wide.

This thesis was based on a prospective follow-up of all patients at Danderyd Hospital who were known or suspected to be infected with a virus of African origin. A majority of the study subjects were African immigrants who were infected before their arrival to Sweden. The subtype of the viruses was determined by phylogenetic analysis of DNA sequences corresponding to the V3 domain of the env gene. We found that almost all known subtypes (A, B, C, D, G, H and AE) were represented at Danderyd Hospital. A majority of the infections had occurred in Africa, but some transmissions of non-B-subtypes in Sweden were also documented. Subtype B, which dominates among Swedish HIV-1 infected homosexual men and i.v. drug users, was rare among the study subjects who mainly were heterosexually infected. Furthermore, we found that two patients from Zaire were infected with an earlier not described subtype. These viruses are now prototypes for a new subtype called subtype J.

Plasma virus load is an important predictor of clinical prognosis. We found that two of three first generation assays for plasma HIV-1 RNA quantification failed to accurately quantify some subtypes e.g. subtype A. This finding limits the use of these assays in many parts of the world. In a later study, we found that newer versions of one of the assays more reliably quantified a majority of samples from all subtypes.

Virus entry into cells requires interactions with the CD4 receptor and certain chemokine coreceptors. We investigated if coreceptor usage differs between genetic subtypes of HIV-1. We found that the ability to infect via the CXCR4 coreceptor predicted a rapid/high, SI virus phenotype for all subtypes. However, CXCR4-positive isolates were rare in subtype C, indicating subtype specific differences in biological properties.

Finally, we compared the rate of disease progression in patients infected with subtypes A through D by analysis of the rate of CD4 cell decline, plasma HIV-1 RNA levels and clinical status. Disease progression among ethnic Africans and ethnic Swedes was also compared. We found that neither genetic subtype of the virus nor the ethnicity of the host was found to significantly influence disease progression. This suggests that the difference in biological phenotype of subtype C isolates does not translate into differences in disease progression.

In summary, determination of the genetic subtype of HIV-1 probably has little value for routine clinical care of individual patients, but provides a powerful tool for monitoring changes in local and global transmission patterns.