Special Coverage: Retroviruses Conference 2006

Earlier treatment and more effective drugs needed in battle against HIV

Study offers insight into viral compartmentalization

A better clinical strategy with HIV care would be to begin treatment soon after infection, an HIV researcher suggests.

Once a patient's CD4 cell count has begun to decline, there will be impairment of immune responses both in the short term and long term effect, says Rafael Zioni, MD, a senior fellow in the department of laboratory medicine at the University of Washington in Seattle, WA.

Early antiretroviral treatment will enable the patient to save more CD4 cells for a better immune response later, Zioni says.

"Once the virus enters the body and the virus starts to replicate, it is able to adapt to a new host," Zioni says.

This adaptation results in the virus increasing its genetic diversity, he adds.

"When you allow the virus to replicate freely without a drug shutting it down in the initial stages, then the viral diversity will be increased," Zioni explains. "By the randomness of the situation, the virus then creates better and better viruses that are able to adapt to different tissues or different cell lines and so on."

Then when the patient finally is treated with antiretroviral drugs, the virus is so diverse that it can more easily adapt to the drugs, Zioni says.

"If you give the drug in the most initial stages then you are able to decrease the viral diversity and slow down the adaptation mechanism and reservoir information," he adds.

Zioni, together with H. Zhu, are the lead investigators of an evolutionary study that observed HIV-1 compartmentalization between monocytes and CD4-T-cells in late infection of untreated and treated patients.1

"So we took 21 patients and looked at virus characteristics to see if the virus was different from the T-cell virus in the blood because if there was no difference that would tell us the virus in the monocytes was similar to the T-cells," Zioni says.

"But we found that the virus in the blood monocytes has a different evolution than the virus in blood T-cells," Zioni says.

The virus is evolving in separate evolutionary patterns with or without treatment, Zioni says.

"Studies have shown that tissue macrophages are much more resistant to the drugs than blood CD4 T-cells," Zioni says.

Blood monocytes, when infected, are able to transfer the virus from the blood to tissue macrophages, which are able to act as reservoirs for harboring the virus, Zioni says.

This led to researchers' interest in the evolutionary point of view of whether HIV-1 variants in blood monocytes tend to compartmentalize over time, Zioni says.

"We found that treatment tends to accelerate the compartmentalization phenomenon, which may explain the difference in replication capacity between blood monocytes and blood T-cells during treatment," Zioni notes.

Treatment is able to shut down the virus, but if it does not shut down the virus equally in the two compartments, then the different compartments would be even louder when you do evolutionary studies, Zioni explains.

The study concluded that HIV-1 in blood monocytes evolved significantly during treatment, and there's a need for new drugs targeting HIV-1 in monocyte-macrophage lineages.1

Both better drugs and better treatment regimens are needed, he says.

"And the second thing is the timing of treatment is important," Zioni notes.

When treatment is initiated very early then the virus becomes less compartmentalized, he adds.

If the treatment starts early, but not early enough, or if the virus is heterogeneous or the drug treatment does not specifically affect this compartment, then we'll see the virus replicating more, and the compartmentalization occurs even faster than expected," Zioni says.

"If we have a drug that is effective against the major CD4 T-cells, but which is not effective on blood monocytes, then we have a compartment that is able to harbor a virus," Zioni explains. "The virus, on one hand, is replicating, and on the other hand, it is able to harbor a virus that is able to go from the blood to the tissue and continue the cycle of creating new reservoirs in the tissue."

The main source of HIV in the brain comes from the blood monocytes infecting the brain and becoming like special tissue macrophages in the brain, he adds.

The goals of HIV treatment are to reduce transmission and provide better outcomes for patients, and very early treatment works better at achieving these goals, Zioni asserts.

"I am of the opinion that if we want a better outcome for our patients, it's better to treat them in the initial stages," Zioni says. "We could reduce the virus' ability to destroy so many CD4 cells in the initial stage and allow us to have better control in the next stage."

Reference:

  1. Zioni R, et al. Diverse genotypes and phenotypes of HIV-1 strains in blood monocytes: replicating viruses with effective antiretroviral therapy. Presented at the 13th Conference on Retroviruses and Opportunistic Infections, held Feb. 5-8, 2006, in Denver, CO. Abstract: 283.