However, they are open to other factors playing a role as well. While the early studies from India suggest that the numbers of HAD may be low, it does occur. And Dr Ranga has isolated viruses from a patient from Bangalore infected with HIV-1C with a severe case of HAD. Interestingly, the virus contained several unusual amino acid substitutions in the envelope glycoprotein that altered cellular tropism (the range of cells it could infect) and was able to form syncytia (clumps of virus or viral particles and cells) in MT-2 cells.
This is interesting because one of the possible molecular mechanisms that had previously been proposed for the increased aggressiveness of HIV-1D is its greater tendency to evolve changes in its envelope protein that allow binding to both CCR5 and CXCR4 receptors, thus allowing subtype D to fuse to a wider range of CD4 cell types.
This change is often seen in people with AIDS with subtype B as well (although it is not necessary for clinical progression), so this finding may simply be another effect rather than the root cause of subtype D’s greater pathogenecity. Nevertheless, once increased tropism is present, CD4 cell counts are more rapidly depleted (possibly because of cell death associated with syncytia).
Dr Ranga said that such a shift to CXCR4 tropism hasn’t really been seen with subtype C virus before. The patient had been infected for about 10 years, had no major opportunistic infections or symptoms aside from dementia, but has unfortunately since died. However, identification of such isolates from one individual does not necessarily mean that this particular shift was responsible for his neurological deterioration.
But another recently published study using from samples from the HIV Neurobehavioral Research Center at the University of California, San Diego patients has reported that a certain polymorphism in gp120, specifically in the hypervariable region of the V3 loop “was a lot more common in individuals who had very severe degrees of cognitive impairment than those who were either normal or had milder degrees of cognitive impairment,” said Dr Ronald Ellis (Pillai). “Interestingly, this particular variant could be present either in CSF or in the plasma.”
Unpublished data from the same researchers found that there was significant variability across clades in the frequency of this particular polymorphism. It was found in 10-11% of the isolates from clade B and D, <1-6% of clade A and in 5% of those with clade C.
Dr Dana Gabuzda of the Dana Farber Cancer Institute presented similar findings, identifying two different HIV envelope glycoprotein variants that enhance HIV’s entry and replication in macrophages and which are associated with dementia in patients.
The first env variant, N283 was found in a high frequency of brains of 43 people with HAD/HIVE (39%; n=330 sequences) but was rare in the brains of 24 people with HIV without HAD/HIVE (8%; n=151 (p<0.001). It appeared to increase the affinity of gp120 for CD4, and increased viral replication in macrophages and microglia. The second variant, D386, was much more commonly found in the blood and lymphoid tissue, rather than the brain, but was more associated with HAD nonetheless. It was found from thirteen HAD patients (26%, n=185) compared with nine non-HAD patients (7%, n=99). This variant is characterised by the loss of a glycan (sugar) that lets it bind to and infect macrophages more readily but not microglia or PBMC.
“This suggests that therapeutics targeting Env-CD4 interactions may be beneficial for preventing CNS infection and neurologic injury in HIV-infected patients,” she noted.
Dr Gabuzda has since analysed viral isolates from different clades from the Los Alamos database. The variant N283 and D386 (no glycan) was found in 49% and 17% of Clade A envelopes (n=59), 7% and 18% of Clade B envelopes (n=176), 0% and 8% of Clade C envelopes (n=122) and in 10% and 8% of Clade D respectively. However, she noted that these were simply samples without any functional data (any record of neurological symptoms in the source patient).