Are some subtypes of HIV more likely to cause neuroAIDS than others?

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Differences in the genetic make-up of some HIV subtypes (or clades, such as HIV-1C, which is most prevalent in southern Africa and India) could affect the risk of developing HIV-related neurological disease (neuroAIDS), according to research presented at the two recent meetings on HIV related neurological problems in Venice, Italy, the “Evolving Mechanisms of HIV Neuropathogenesis in the HAART Era: Domestic and Global Issues” meeting and the “Second HIV Infection and the Central Nervous System: Developed and Resource-Limited Settings” meeting.

The preliminary findings could explain why some studies have observed lower rates of neuroAIDS among people with HIV-1C than were reported in people with HIV-1B in industrialized countries before HAART became available.

However other experts at the meetings remain unconvinced that there are any major differences in disease caused by the different clades of HIV-1 — and said more careful and systematic research could find the prevalence of HIV-related minor cognitive motor disorders (MCMD) and the more severe HIV-associated dementia (HAD) in people with advanced HIV-disease to be roughly similar in resource-limited settings and in industrialised countries (whatever the clade).

Glossary

subtype

In HIV, different strains which can be grouped according to their genes. HIV-1 is classified into three ‘groups,’ M, N, and O. Most HIV-1 is in group M which is further divided into subtypes, A, B, C and D etc. Subtype B is most common in Europe and North America, whilst A, C and D are most important worldwide.

neurological

Relating to the brain or central nervous system.

clades

The term for the different sub-types of HIV.

dementia

Loss of the ability to process, learn, and remember information. Potential causes include alcohol or drug abuse, depression, anxiety, vascular cognitive impairment, Alzheimer’s disease and HIV-associated neurocognitive disorder (HAND). 

matched

In a case-control study, a process to make the cases and the controls comparable with respect to extraneous factors. For example, each case is matched individually with a control subject on variables such as age, sex and HIV status. 

“The null hypothesis — that there really isn’t any difference in clades (they all come from one place, they haven’t had a lot of time to diverge from one another) — is going to be difficult to disprove,” said Dr Ron Ellis, who is the director of the HIV Neurobehavioral Research Center (HNRC), at the University of San Diego, which is helping to coordinate some of the international research into the effects of HIV clades upon HIV neurological diseases.

Nevertheless, he and several other researchers explained the case for conducting this research, some of the possible mechanisms that could explain differences between clades, as well as the many challenges in performing this kind of research in the, sometimes, disparate HIV-infected populations in different parts of the world.

The observed patterns in neurological disease

“Many people believe there is a difference in the number of HIV dementia cases that you see between subtype C in India and subtype B in Europe and US,” said Vinayaka Prasad of the Albert Einstein College of Medicine in New York.

One of the definitive papers on HAD before HAART, by McArthur et al in Neurology in 1993, suggested that the incidence of HAD (in subtype B) was about 15-30%. However, Prasad said that early reports where subtype C is prevalent have not yet reported such high rates.

“There are many new papers that have come out of India recently which come up with various numbers but all appear to be less than 6%,” he said. He noted several, including a paper from Satishchandra P et al (2000) in IJMR, 111:14-23 which reported HAD in 2 out of 100 cases; a paper from Wadia RS et al, (2001) in J. Assoc. Physicians India 49:343-8, which found only 21 cases in 1527 cases (1.4%); and a paper by Deshpande AK and Patnaik MM (2005) in Med. Gen. Med, which reported HAD in 18 out of 300 patients with HIV, (5.9%).

“But really good incidence reports for India are still being initiated currently,” Prasad continued, “and I think the jury is out.”

There has been a dearth of neurological research in parts of the world where non-subtype B strains are more prevalent so whether the incidence is lower elsewhere in the world is unclear. One older international study conducted in Brazil (subtypes B and F), Kenya (subtypes A and D), Zaire (variety of subtypes) and Thailand (subtype E) by the World Health Organisation reported relatively consistent rates of neurological disease (13-19%).

Meanwhile, a recent study from Dr Ned Sacktor of John’s Hopkin’s University reported that around 31% of Ugandans (presumably infected with subtypes A and D) had HAD.

But a study by Dr. David Clifford of Washington University in Missouri, reported that there was no significant difference between Ethiopians infected with HIV-C and HIV-negative people from the local community, matched for age, education and other potential confounders.

“We had one of the best designed studies, with a well characterised cohort matched to local controls,” Dr. Clifford told this reporter, “and we didn’t see a thing.”

However, it has been previously pointed out that this cohort had less advanced disease than some (with a median of 270 CD4 cells/mm3) so it is possible that, with follow-up, changes might have been observed. Unfortunately we’ll never know. Dr Clifford says the funding for this study ran out, the team of local researchers has dispersed (hired away to other projects) and the cohort has been lost.

This is especially unfortunate because so few researchers have bothered to investigate this issue in Africa.

“The epidemiology of neuroAIDS in Africa remains largely unknown 27 years after the start of the epidemic,” said Georgette D Kanmogne, a scientist at the University of Nebraska Medical Center who is from Cameroon. But Kanmogne has recently received a NIH grant to begin investigating HIV-related neurological disorders in her home country — a hot bed for HIV diversity since it contains all known HIV types, groups, subtypes and many of the circulating recombinant forms (CRFs).

But why might viral diversity make a difference in neurological disorders? To read more, see part two of this article.

Related articles

Part two - HIV dementia: why might some viruses cause more problems than others?

Part three - HIV dementia: are viral or host factors driving differences between subtypes? (full references to all articles in the series can be found in part three).