The results of our study suggest that, among HIV-infected individuals with advanced immunosuppression at risk of developing cognitive impairment, HIV dementia is more common among subtype D–infected persons than among subtype A–infected persons, as determined by phylogenetic analysis of both the gag
regions. These findings provide, to our knowledge, the first direct evidence in well-characterized HIV-infected individuals at a similar stage of HIV disease that HIV subtypes may have a different biological impact on neurological complications of HIV infection—namely, HAND. These results are consistent with previous data suggesting that HIV subtype D may be associated with more-rapid HIV disease progression—specifically, a lower CD4 cell count during follow-up and a faster progression to death—compared with subtype A. In a study of 140 HIV-infected seroconverters in Rakai, Uganda, 59% of subtype D–infected subjects experienced progression to AIDS or died, whereas 29% of subtype A–infected subjects experienced progression to AIDS, and none died [3
]. Similar results were seen in another study of 1045 HIV-infected individuals in Uganda in which subtype D infection was associated with a lower CD4 cell count during follow-up and a faster progression to death [4
]. Also, in a study from Senegal, the incidence of AIDS was 14.5 cases per 100 person-years for subtype D–infected individuals, 16.0 cases per 100 person-years for subtype C–infected individuals, and 3.5 cases per 100 person-years for subtype A–infected individuals [2
]. Another study of 428 HIV-infected women in Tanzania also found that subtype D–infected individuals experienced more-rapid progression to a CD4 cell count ≤200 cells/μ
L and World Health Organization stage 4 illness and a higher mortality rate, compared with subtype A–infected individuals [2
]. These data suggest that HIV subtypes may differ with respect to virulence and the risk of HIV-associated complications from advanced immunodeficiency.
A limitation to the study is that HIV-infected individuals at risk of developing cognitive impairment were involved in the study. They had abnormal performances on a screening test for HIV dementia (IHDS, ≤10), suggestive of HAND, and CD4 lymphocyte counts <200 cells/μ
L. However, dementia is primarily observed in patients with advanced immunosuppression (CD4 lymphocyte count, <200 cells/μ
L). In addition, our subtype distribution for the subjects studied in Kampala is remarkably similar to the subtype distribution of the polymerase gene among 279 women who attended a prenatal clinic in Kampala (subtype A, 53%; subtype D, 35%; subtype C, 2%; and recombinants, 10%) [21
]. Nevertheless, the finding that 89% of subjects infected with subtype D had evidence of dementia, compared to 24% of those infected with subtype A, suggests that subtype D is associated with an increased risk of dementia. Additional studies need to be performed to determine whether the risk of HIV dementia is increased for subtype D versus subtype A among all HIV-infected individuals in Uganda.
One hypothesis for this differential rate of progression for HIV subtypes relates to differences in coreceptor use. HIV subtype A and subtype C favor the chemokine receptor CCR5 for viral entry throughout the course of infection [2
]. The use of CCR5 receptors seen in subtype A and C correlates with a nonsyncytium inducing macrophage-tropic version of HIV, which is associated with slower viral growth and replication [2
]. In contrast, HIV subtype D displays a tropism for the syncytium-inducing chemokine receptor observed principally in T cells [2
] and possibly a dual tropism for both coreceptors [2
]. CXCR4 T cell tropic strains are associated with more-rapid viral growth and replication, which could allow subtype D to infect more cells per unit of time than other subtypes, allowing for more-rapid HIV disease progression [2
With respect to potential mechanisms for a differential rate of neurovirulence by subtype, one possible mechanism relates to the tat
gene. Recent data suggest that the tat
gene in subtype C is associated with increased cell survival in rat hippocampal neuron cultures, compared with in subtype B [25
], but the relative neurotoxicity of other clades, such as A and D, requires further study. The neurotoxicity of tat
may occur through binding of the NMDA receptor, allowing for calcium-induced excitotoxicity, increased apoptosis, neuronal injury, and death. Another possible mechanism for an increased risk of neuro-pathogenesis from subtype D relates to differences in the V3 loop of the envelope gene [2
]. The hypervariable V3 loop of the envelope glycoprotein gp120 is involved in HIV entry into the CD4 cell, and clade D strains have been identified with a more-variable pattern of V3 loop amino acids than other subtypes [2
]. Viral envelope diversity can influence the progression of neurological disease in several other retroviruses [2
], and similar effects may be seen with the HIV envelope gene [2
]. HIV dementia–associated strains differ predominantly in the V1 and V3 region of the gp120 envelope protein, which are the same regions that account for HIV subtype diversity [2
]. Of note, in the phylogenetic analyses for subtype determination in this study, subtype D was associated with an increased risk of HIV dementia in the gp41
envelope gene, whereas only a trend was seen for an increased association of subtype D for HIV dementia in the gag
gene. These results suggest that the envelope gene may be more critical for conferring an increased risk of HIV dementia than is the gag
gene in subtype D–infected individuals. Differences in coreceptor use and syncytium inducibility as described above could also account for differences in neurovirulence.
The genetic diversity of the HIV virus is due to many factors, including its high replication rates, lack of a proofreading capacity with mismatch errors, and a propensity for recombination [2
]. The HIV virus has more genetic diversity and interclade recombination occurs more frequently in Africa than in the United States [2
]. Thus, Africa is an ideal setting to examine issues related to subtype and the risk of HIV dementia. In Uganda, where 2 HIV subtypes predominate, our results suggest that subtype D is associated with an increased risk of HIV dementia. Additional studies are needed to confirm this observation. The precise mechanism by which subtype D leads to an increased risk of HIV dementia remains to be elucidated, but differences in the tat
gene, envelope gene, coreceptor use, and syncytium inducibility may be involved. Additional studies are needed globally to define the frequency of HIV dementia in all subtypes and to define the rate of progression of HAND within specific HIV subtypes. The effect of HIV subtype on other neurological complications of HIV infection, such as sensory neuropathy and opportunistic infection of the central nervous system, also should be examined.