The human immunodeficiency virus (HIV), discovered 25 years ago, has emerged as the most intensely investigated virus in all of human history. Despite this, it remains a biological mystery. One unsolved riddle had been a change in the molecular address the gateway that HIV uses to enter its target cells in the human body. The change is widely seen in the West, but almost never in India.
Now a team of biologists in New Delhi and Chandigarh has come up with a possible explanation for why this switch in the gateway isnt observed in Indians: high levels of background infections. Their study has provided fresh insights into the evolutionary tricks that HIV has acquired to continue multiplying in an infected person, while constantly evading destruction.
This is primarily an exploration of the basic biology of HIV, but it could also have ramifications for future strategies to treat infected people, said Shahid Jameel, the head of Virology at the International Centre for Genetic Engineering and Biotechnology, New Delhi, who led the study. The findings have just been published in the Journal of Clinical Virology.
The virus uses two key protein molecules to enter its target human T-cells the main CD4 receptor protein, and a receptor called CCR5 (or R5). They are found on the surface of some T-cells and serve as molecular gateways required for the virus to slip inside the cells. The infection starts with HIV being capable of using the R5 protein.
Previous studies in Western populations, most of them conducted in the United States, have shown that as the infection progresses over time in an infected person, the virus multiplies and evolves and loses its ability to exploit R5, but begins to use another surface protein called CXCR4, or X4, to invade T-cells.
About half of HIV in late infection among Western populations are viruses that use X4. The switch appears to coincide with the advance of the infection to the full-blown AIDS, the onset of life-threatening infections that mark the end stage of the illness.
But virtually all viruses from Indians and some African populations display no such gateway switch from R5 to X4.
This switch takes places to maximise the infectivity of HIV, said Jameel. After the initial infection, HIV has to multiply and infect more T-cells. But not all T-cells have R5 on their surface.
Infections can activate T-cells, triggering the appearance of R5 on them. Most people in India are constantly exposed to a high burden of infections viral, bacterial, parasitic and thus have a high load of T-cells with the R5 protein to fight off such infections.
Since there are plenty of cells with the R5 protein in Indian patients, there is no evolutionary pressure on the virus to make the switch towards X4, Jameel said. His team at the ICGEB and a collaborator, Ajay Wanchu of the Postgraduate Institute of Medical Education and Research, Chandigarh, examined the T-cells from 40 HIV positive people who had not started any drug therapy.
The researchers also found that T-cells in infected Indians show less of the R5 protein than in infected Westerners. Viruses that use R5 tend to reduce levels of R5 protein in infected people, while viruses that use X4 tend to reduce the X4 protein.
This could be a survival strategy of the virus, Jameel said.
It might be an adaptation to prevent infection of the same cell with more than one virus which, he said, can be detrimental to the virus.
Infection by multiple viruses can trigger a death response which no longer supports viral replication, he explained.
But some researchers believe that results from studies that rely on T-cells from the bloodstream need to be viewed with caution because the infection is actually in the lymphatic system such as the lymph nodes. The vast majority of the T-cells are in lymphatic tissues, and not in blood, said Udaykumar Ranga, a virologist at the Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore.
The T-cells from blood are not representative of the T-cells in the lymphatic system, Ranga said. However, most similar studies have used T-cells from blood because it is not ethically possible to get T-cells from the lymphatic system, which would require conducting a biopsy on an infected persons lymph nodes. This is a technical limitation of such studies, Ranga said.
Studies to investigate the switch from the R5 to the X4 receptor are primarily basic research, aimed at exploring how HIV interacts with its human host. But the absence of this switch among Indian patients may have clinical ramifications for future ways of treating HIV infected patients, said Jameel.
A drug that specifically deactivates or blocks the R5 receptor might turn out to be useful in populations where the switch from R5 to X4 does not take place, such as India. Such a drug could be effectively used in our patients since HIV strains in our population infect exclusively through R5 and not through X4, Jameel said.
But with HIV, no one is willing to place bets. It would be interesting to see if the virus switches to X4 or not in patients treated with such a drug, he said.