Fwd: CATIE-News - HIV-challenges to a cure

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CATIE-News - HIV—challenges to a cure

 

HIV infection results in the loss of key immune system cells. This virus gradually turns the immune system against itself, and within an average of 10 years after initial infection with HIV, the body is unable to defend itself against many different types of germs. In untreated HIV disease, life-threatening complications are the result.

 

Today, combination anti-HIV therapy, called highly active antiretroviral therapy (HAART), is widely available in most high-income countries. In these countries, AIDS-related infections are uncommon, at least among people who are aware of their HIV status, are engaged in regular medical care, and can adhere to and tolerate HAART.

 

Therapy for HIV is very good at suppressing production of new copies of HIV down to very low levels. However, despite many years of therapy, HAART has not cu

red HIV infection. And once a person stops taking HAART, virus levels once more soar in the blood and tissues.

 

Still, research teams in several countries are studying ways of eradicating or curing HIV infection. This interest has continued despite many setbacks at attempted cures over the past two decades. Before delving into recent reports of apparent cures for HIV/AIDS, we review some of the obstacles to achieving this.

 

The reservoir of T-cells

Researchers who have been struggling to cure HIV infection have come up against a difficult barrier. It seems that despite the type of HAART and length of time it’s used, HIV persists deep within the body in lymph nodes and tissues. One team of virologists estimates that there are about one million infected CD4+ T cells in the bodies of people taking HAART who have very low viral loads (less than 50 copies/ml of blood). Recent research suggests that this reservoir may be established very early in the course of HIV infection, long before therapy begins.

 

Finding and wiping out all of these HIV-infected cells will not be easy because only 2% of HIV is found in the blood. The vast majority resides in immune cells in lymph nodes and tissues.

 

Beyond T-cells

In addition to T-cells, other types of immune cells also have the CD4+ receptor on their surface, which allows HIV to enter and infect them. These include monocytes/macrophages, dendritic cells and possibly other cells. Anti-HIV drugs do not work well in macrophages, so it is possible that these cells could serve as another reservoir for HIV. Troublingly, macrophages can rove around the body and enter and exit organs such as the brain. There, they may be shielded from the effects of anti-HIV drugs, as many of these medicines do not easily penetrate the brain. Moreover, the lining of the brain contains tiny pumps that flush out compounds—including many anti-HIV drugs—once they do enter the brain.

 

Latent, but not for ever

In people taking HAART, HIV can be found in resting CD4+ cells deep inside the body’s lymph nodes and tissues. There, the virus stays dormant until some signal, perhaps from the stimulation of an infection, allergy or vaccine, awakens the cell. Once stimulated, HIV turns the cell into a mini-virus factory whic

h releases new viruses and in the process dies. The release of new viruses allows HIV to infect new cells and this helps to sustain this virus’ presence in the body.

 

Problems with “undetectable†viral loads

In high-income countries, commonly available tests to assess viral load can accurately count down, depending on the test used, to between 40 and 60 copies/ml of blood. Below this lower limit, the tests might be able to detect HIV but cannot accurately count it. Some people have taken to calling their viral loads that are below the lower limit of detection “undetectable.†This gives the mistaken impression that HIV is somehow absent. However, that may be about to change.

 

Leading virologists in the United States have developed a very sensitive research assay that can accurately detect and count viral loads as low as a single copy. This test is called a single copy assay. Using this highly sensitive test, the virologists assessed blood samples taken from 130 people who were participating in a clinical trial of HAART. All of these people had their viral loads continuously suppressed (that is, below the lower limit of detection of a conventional test) for up to 60 weeks.

 

The team then analysed the blood samples using the single copy assay and found that, on average, viral load in people considered suppressed (with a conventional test) was about 3 copies. This suggests that in most participants HIV was infecting new cells and that these cells were producing new copies of HIV, albeit at low levels. Overall, about 80% of participants formerly considered virologically suppressed were in fact still producing HIV. The study team found that this was the case whether people were using regimens based on protease inhibitors or non-nukes (NNRTIs).

 

The study team then obtained more blood samples, as participants continued in the clinical trial for more than 60 weeks (in some cases as long as two years), and found that, essentially, there was no further change to viral loads. That is, although conventional tests continued to show that these people had viral loads below 50 copies, the single copy assay uncovered low-level HIV replication.

 

The team of virologists concluded that “few patients on antiretroviral therapy have ‘undetectable’ [virus] if suffic

iently sensitive assays are [used].â€

 

Several other research teams have concluded that currently available regimens—no matter how intense—are unlikely to cure or eradicate HIV. Rather, it might be more useful to identify each reservoir of HIV and find ways of targeting HIV within that reservoir.

 

In the next CATIE-News story, we focus on a medically popular but failed way of trying to cure HIV infection—intensive radiation and/or chemotherapy followed by a bone marrow transplant.

 

— R. Hosein

REFERENCES:

1. Marsden MD, Zack JA. Eradication of HIV: current challenges and new directions. Journal of Antimicrobial Chemotherapy. 2008; in press.

2. Palmer S, Wiegand AP, Maldarelli F, et al. New real-time reverse transcriptase-initiated PCR assay with single-copy sensitivity for human immunodeficiency virus type 1 RNA in plasma. Journal of Clinical Microbiology. 2003 Oct;41(10):4531-6.

3. Maldare

lli F, Palmer S, King MS, et al. ART suppresses plasma HIV-1 RNA to a stable set point predicted by pretherapy viremia. PLoS Pathogens. 2007 Apr;3(4):e46.

4. Shen L, Siliciano RF. Viral reservoirs, residual viremia, and the potential of highly active antiretroviral therapy to eradicate HIV infection. Journal of Allergy and Clinical Immunology. 2008 Jul;122(1):22-8.

5. Sedaghat AR, Dinoso JB, Shen L, et al. Decay dynamics of HIV-1 depend on the inhibited stages of the viral life cycle. Proceedings of the National Academy of Sciences USA. 2008 Mar 25;105(12):4832-7.

6. Joos B, Fischer M, Kuster H, et al. HIV rebounds from latently infected cells, rather than from continuing low-level replication. Proceedings of the National Academy of Sciences USA. 2008 Oct 28;105(43):16725-30.

7. Palmer S, Maldarelli F, Wiegand A, et al. Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy. Proceedings of the National Academy of Sciences USA. 2008 Mar 11;105(10):3879-84.

 

 

 

 

 

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