Cell-to-cell spread of HIV and its possible implications for antiretroviral therapy

BK

Today’s post features a conversation with an inspiring person about HIV transmission, health inequality in sub-Saharan Africa, and future directions for HIV control. Dr Boghuma Kabisen Titanji is a physician from Cameroon with a deep caring for people and how research can affect their lives. Boghuma has an MSc in Tropical Medicine and International Health from the London School of Hygiene and Tropical Medicine, and she is currently a Commonwealth Scholar completing her PhD in Infectious Diseases at University College London.

 

Why did you decide to make the transition from a medical doctor to HIV researcher?

My first encounter with HIV research was in the final year of my medical training at the University of Yaoundé, in Cameroon, when I did a fellowship at the Centers for Disease Control and Prevention in the United States. My research project was on the development of drug resistance following the use of prophylactic antiretrovirals for the prevention of mother-to-child transmission of HIV. This experience made a lasting impression on me because although it was a small study of 40 patients, we were able to feed back the information from the study to the clinic in Cameroon where HIV-positive mothers were receiving pre- and post-natal care. That information was used to adjust their treatments and take them off of the drugs that were no longer effective due to the development of drug resistance. Because they were part of the study we were able to get the tests done, which they would normally not have been able to afford. That struck a chord in me about the importance of linking research to clinical practice, especially in my environment. After two years of clinical work, I decided to do my PhD to get more HIV research training.

Your research paper titled ‘Protease inhibitors effectively block cell-to-cell spread of HIV-1 between T cells’ was recently published in the journal Retrovirology and is already one of its most highly cited articles (1). The paper shows that a certain class of antiretroviral drug inhibits the spread of HIV directly between cells within the body. What was the rationale for this study?

Antiretroviral therapy (ART), which is given as a combination of drugs, is the current treatment we have for HIV. ART reduces the spread of HIV within the body to make it a manageable chronic disease. When I started my PhD in 2011, it had just been discovered that although ART reduces ‘cell-free’ spread of HIV within the body, it is less effective at reducing ‘cell-to-cell’ spread (2). Cell-free spread is the classical way in which HIV particles spread by diffusing in the bloodstream and local environment to infect cells. The virus also has the ability to spread directly from cell-to-cell. Cell-to-cell spread occurs when an infected cell forms a stable point of contact with an uninfected cell and transmits HIV particles directly to the uninfected cell. Cell-to-cell spread is more efficient, quicker, and does not require diffusion in the bloodstream, compared to cell-free spread. Basically, cell-to-cell spread equals good news for the virus, but very bad news for us.

Cell-free spread of HIV: the HIV virions diffuse through the bloodstream, and attach to receptors on the surface of uninfected cells, then enter the cell to infect it

Cell-free spread of HIV: the HIV virions (in yellow) diffuse through the bloodstream, and attach to receptors on the surface of an uninfected cell, then enter the cell to infect it

This is an interesting paper for a number of reasons, one of which is something that many people don’t understand: although treatment reduces the multiplication of the virus, HIV forms ‘reservoirs’ within the body, which make it impossible for existing drugs to eliminate the virus from the body. Researchers are constantly seeking ways to improve existing treatments and to understand how and why these HIV reservoirs persist. My research group and others now think that ongoing cell-to-cell spread within HIV reservoirs is maybe one of the reasons why ART does not cure HIV.  It had already been shown that one class of ART drugs called Reverse Transcriptase Inhibitors (RTIs) were ineffective in preventing cell-to-cell spread. The effect of Protease Inhibitors (PIs), another class of antiretroviral drug, on this mode of virus spread, was not known. PIs are potent antiretroviral drugs, which are commonly used in treatment combinations and for second-line therapy when first-line RTI-based combinations fail. Their mode of action is different from that of RTIs, so it was interesting to investigate whether PIs could inhibit cell-to-cell spread of HIV.

Cell-to-cell spread of HIV: the HIV particle (in yellow) is spread from an infected cell directly to an uninfected cell

Cell-to-cell spread of HIV: the HIV virions (in yellow) are spread from an infected cell directly to an uninfected cell

What were the main findings of your study?

We were able to show that all drugs are not the same in terms of blocking cell-to-cell spread . Confirming previous reports, the RTIs were inefficient in blocking cell-to-cell spread of HIV in this study. By contrast, we found that the PIs were equally effective in blocking both cell-to-cell and cell-free spread. This is an important finding because it gives us an idea of which drug class is most likely to reduce cell-to-cell HIV spread.

In the clinic, RTIs and PIs are administered together to HIV patients in a combination, rather than as single drugs as you’ve tested here. Are you planning to test actual combinations that are given to patients to see how these drugs might work in clinical practice?

Yes. It is important to test the impact of different combinations of antiretroviral drugs on all modes of virus spread. If a particular combination of drugs is less effective in blocking one method of spread than another, then administering the less effective combination to patients may facilitate the emergence and proliferation of drug resistant viruses. To elaborate on this work, I will test drug combinations containing PIs, which are commonly used in the clinic to see how well they block the different modes of HIV spread. We would like to inform on the best combination of drugs to use in treating patients. Another HIV research group has recently tested several different combinations of RTIs on cell-free and cell-to-cell spread and they saw a synergistic effect – drugs acting in combination work better than drugs acting alone against cell-to-cell spread (3).

Obviously, your research shows that PIs might be more effective than RTIs in blocking cell-to-cell spread. Why are PIs often second line therapy in Africa when they are the only class of drugs approved to be given alone as monotherapy?

A ‘public health’ approach is recommended for the treatment of HIV in Africa. We have to focus on getting effective treatment to the greatest number of patients and cannot do personalised treatment. For example, if you have HIV and you live in the UK, you get drugs free of charge to start with. You will get top end triple-therapy (three drugs), where your first line of treatment would consist of RTIs and a PI. If the first line treatment fails, you will have options for second, third, and even fourth line treatments – just because they are available and the National Health Service covers the cost.

The use of PIs as monotherapy is reserved for patients with very well-defined clinical characteristics and is not generalizable to the large numbers of patients in sub-Saharan Africa. In Africa, it’s different. The first line consists of RTIs only. Drug combinations containing PIs are reserved for second-line treatment when RTIs fail. There is a very limited pool of drugs available to the treatment programs in sub-Saharan Africa and this makes the options for third and fourth line treatments virtually non-existent. Some of the newer drugs such as Integrase Inhibitors are simply not available in that environment due to their cost. We need to use limited resources wisely, especially in the context of a weak and resource-limited healthcare system.

What could be the future public health and HIV policy implications of your work?

Knowing that different classes of antiretroviral drugs have variable effects on cell-to-cell spread, with some being effective and some being less effective is useful information, as we think this will need to be considered in future therapeutic strategies for treating HIV. It is  important to note that studies like this, while informative, are done in-vitro and we only  know for sure what works through clinical trials which assess the efficacy of drug combinations in actual patients. Over the last 10 years the role of cell-to-cell spread of HIV has become increasingly recognised, and in-vitro studies such as this, will allow drugs still in development to be tested on their ability to block all modes of virus spread.

Any final words?

HIV/AIDS has come a long way – we are 30 years into the epidemic and in that time intensive research efforts have transformed what used to be a death sentence into a manageable chronic condition with treatment. We should not lose sight of the fact that there are still many people who need these life-saving drugs and are not getting them. Whatever we are able to show in the lab is useful, but the main challenge remains translating this information into the clinic to improve outcomes for those most affected by the disease, especially in resource-limited sub-Saharan Africa. The best treatment and the same standard of care should be available everywhere – a patient diagnosed in London should have the same options as a patient diagnosed in Cameroon, and we are not there yet.

References

1)      Titanji BK, Aasa-Chapman M, Pillay D, Jolly C. Protease inhibitors effectively block cell-to-cell spread of HIV-1 between T cells. Retrovirology 2013;10:161

2)      Sigal A, Kim JT, Balazs AB, Dekel E, Mayo A, Milo R, et al. Cell-to-cell spread of HIV permits ongoing replication despite antiretroviral therapy. Nature 2011; 477(7362):95-8.

3)      Agosto LM, Zhong P, Munro J, Mothes W. Highly active antiretroviral therapies are effective against HIV-1 cell-to-cell transmission. PLOS Pathogens 2014;doi: 10.1371/journal.ppat.1003982

Images created by BK Titanji

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One Response to Cell-to-cell spread of HIV and its possible implications for antiretroviral therapy

  1. Mojaver says:

    In your paper, you refer to the fact that protease inhibitors effectively inhibit cell-to-cell transfer of HIV-1.
    And we know that protease inhibitors prevent HIV protease from cleaving the HIV polyprotein into functional units, causing infected cells to produce immature virus particles that are noninfectious.
    How does this drug have an effect in the cell-to-cell spread of HIV-1?
    Do protease inhibitors in the cell-to-cell spread of HIV-1 make the T-cells noninfectious that is in the model do we have two class of infected T-cells:infectious and noninfectious ones?
    If else, How this kind of drug have an impact in the infected T-cells?

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