Ugandans infected with HIV subtype D are more likely to experience rapid disease progression to AIDS or death than those infected with subtype A, according to a study reported at the Thirteenth Conference on Retroviruses and Opportunistic Infections in Denver. This effect was independent of viral load for the first two years after infection.
According to the study’s presenter, Dr Oliver Laeyendecker of the National Institutes of Allergies and Infectious Diseases (NIAID) and Johns Hopkins Medical Institute, the greater virulence of subtype D was also associated with a switch to dual tropic virus, which uses both the CCR5 and the CXCR4 receptors and can infect a wider range of blood cells (see below).
Viral subtype background
Different strains of HIV can be grouped according to their genes. HIV-1 group M is the most common globally but the group is further divided into subtypes A, B, C and D, etc. Subtype B is commonest in the United Kingdom, Europe and the Americas, whilst A, C and D are prevalent worldwide. Previous studies have shown that different HIV subtypes can have differing effects on transmission, the development of resistance and disease progression.
Earlier studies have suggested that HIV subtype D depletes CD4 cells and causes disease more rapidly than subtype A. However, these studies did not control for viral load or look at recombinant viral strains (when two or more viral subtypes merge as a result of coinfection) that incorporate subtype D.
Some researchers have proposed that a difference in co-receptor tropism could be to partly to blame for a difference in virulence between subtypes, but this is quite controversial.
Regardless of subtype, people usually become infected with HIV that enters the cell through the CCR5 co-receptor, which is common on the surface of some white blood cells, such as macrophages, but is not present on all CD4 cells. A switch to use of the CXCR4 receptor often occurs later in HIV infection and is associated with more rapid disease progression and loss of CD4 T-cells. When some of the virus makes this switch to use of the CXCR4 receptor, the viral population is termed “dual tropic.”
However, expert opinion has been divided over whether the appearance of dual tropic HIV precedes immunological deterioration and disease progression or comes as a consequence of it, or, perhaps, that a little bit of both occur. Several studies have shown that significant CD4 cell depletion occurs before the evolution of dual tropic virus. Likewise, it has never been demonstrated that any viral subtype such as subtype D has a greater genetic propensity to switch to dual tropism, only that dual tropism has been observed with greater frequency in people infected with certain viral subtypes.
Of the 340 newly infected individuals, 60% were infected with subtype D, 16% with subtype A, 20% were infected with recombinant viruses, 4% were dually infected with a mixed population of viruses. (Subtype C, a rather recent introduction into the Ugandan population, was not observed in this study).
The median age of infection or viral load did not differ based upon the subtype with which the individual was infected.
The Ugandan subtype study
The data Dr Laeyendecker presented were from a retrospective study of the Rakai Uganda Cohort, a population based cohort of 12,000 individuals from over 50 communities in the Rakai region who are studied annually. Between 1994 and 2001, 340 newly infected individuals were identified in the cohort by annual blood draws.
The study examined the patients' viral subtype using a multi-region hybridisation assay (MHA), specific for subtypes A, C and D, the strains endemic to Uganda. The MHA assay is a rapid way to screen the entire viral genome for the viral subtype, recombinant viruses and dual infections.
Patients were followed to monitor progression to AIDS (defined as having a CD4 cell count below 250 cells) and death.
Over more than five years of follow-up, there were 23 deaths, and 60 cases of AIDS. Based on Kaplan Meier survival curves, there was a significant difference in time to AIDS and death between subtype A and subtype D and recombinant viruses. The median time to AIDS or death was 8.8 years for subtype A , 6.9 years for subtype D, and 5.8 years for recombinant viruses.
Based on a Cox proportional hazards regression analysis for AIDS and death, subtype D and recombinant viruses had an adjusted hazard ratio of 2.9 and 4.9 even while controlling for viral load. Viral load was also a significant predictor of progression in this model, while gender, age or infection with multiple strains were not (although the number with mixed strains was to small to reach any definitive conclusions).
Of the individuals for whom outcome data were available, only 40% of individuals with subtype D or recombinant viruses were healthy compared to 75% of of those infected with subtype A.
“When looking at rapid death, roughly 10% of individuals infected with subtype D or a recombinant strain that incorporated subtype D were dead within three years. When comparing the viral load for those individuals who died versus those who individuals who were alive after three years, there was a slightly elevated viral load in those who died versus those who didn’t, but this difference was not significant,” said Dr Laeyendecker.
Viral tropism sub-studies
Data on viral tropism were available in 31 newly infected patients. Within two years of infection, five of 31 individuals had dual tropic virus. All five had subtype D, and of the individuals with dual tropic virus, four out of five were dead within three years of infection.
Then, in a population based assessment of chronically and newly infected individuals, roughly a quarter of those with subtype D and 16% of those with recombinant viruses had dual tropic virus. From the time that this viral tropism was determined, 68% of the individuals with dual tropic virus were dead within three years.
And yet, the data could not show that dual tropism was the cause of subtype D’s greater pathogenecity, only that it was associated with it.
However, it is clear that subtype D and recombinant strains of subtype D put patients at increased risk of progression, rapid death and a shift to dual tropism.
“Determination of HIV subtype is therefore important for the management of HIV infected individuals because disease progression occurs more rapidly in individuals with subtype D or recombinant stains of the virus which incorporate subtype D than other strains. Vaccine trials or trials of antiretroviral treatment which assess disease progression as an endpoint must consider subtype differences,” Dr Laeyendecker concluded.
Laeyendecker O et al. The effect of HIV subtype on rapid disease progression in Rakai, Uganda. Thirteenth Conference on Retroviruses and Opportunistic Infections, Denver, abstract 44, 2006.