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Answer by Tirumalai Kamala:

Interesting question as in how could immune suppression induced by retrovir go hand in hand with the immune activation required to clear Kaposi’s sarcoma (KS)? Let’s clarify two misconceptions though.

One, HIV is an RNA virus and retrovir targets its reverse transcriptase enzyme. OTOH, KS is associated with human herpesvirus 8 (HHV-8), a DNA virus, which lacks this enzyme. Ergo, retrovir does not directly treat HHV-8-associated KS. Two, clinical signs of KS indicate full-blown HIV disease (AIDS), not simply HIV carriage (HIV/AIDS).

Moving along, let’s examine retrovir, HIV and KS to better understand how they intersect. First, what is retrovir? Next, what is KS and how is HIV-associated KS treated? Finally, how is KS associated with HIV?

What is Retrovir? 3’-azido-3’-deoxythymidine (AZT).
Also called Zidovudine, sold as Retrovir and Retrovis, how did AZT become an anti-HIV Rx? Drug re-purposing. Developed for one disease. Didn’t pan out. Decades later, found to be useful against another disease.

  1. In 1964, Jerome Horowitz Jonathan Chua, and Michael Noel synthesized AZT as an anti-cancer drug (1). Side-effects, particularly anemia so sidelined for decades.
  2. In 1985, a team at the US NIH found AZT’s effectiveness against HIV. It blocked its reverse transcriptase, an enzyme necessary to replicate its RNA (2).
  3. Glaxo Smith Kline (then Burroughs-Wellcome) purchased the AZT formula and filed a patent in 1986 (3).
  4. These were the days of the HIV panic. Unsurprisingly, US FDA fast-tracked drug approval. March 20, 1987, to be precise. First for treatment. Later in 1990 also for prevention (3).

Not all good news though. One, AZT has several side-effects. Two, HIV quickly developed anti-AZT resistance.

From 3
Some side-effects were related to dose. Initially 400mg of AZT every four hours. Anemia a frequent side-effect. Now much lower doses are used, and in combination with other drugs. This reduces its more serious side-effects.

What is Kaposi’s sarcoma (KS) and how is it treated?

  1. Moritz Kaposi, a Hungarian dermatologist originally observed it in 1872 as ‘idiopathic multiple pigmented sarcoma’ of the skin (4)
  2. In the 1920s more frequently observed in East and Central Africa.
  3. Non-uniform distribution across Africa suggested an infectious origin.
  4. Giraldo et al found herpes-like virus particles in skin biopsies (5).
  5. In the early 1980s, sudden explosion in KS cases in the West, particularly in gay men (6, 7).
  6. Such KS cases associated with newly recognized syndrome, HIV-associated AIDS (6, 7).
  7. In 1994, Yuan Chang and Patrick Moore’s group isolated a previously unknown herpesvirus from an AIDS patient (8). Today, we call it human herpesvirus 8 (HHV-8).
  8. Some, not all, HIV-positive who are also HHV-8 positive and who progress to AIDS develop KS. Why some and not all? Not yet clear.
  9. Today, clinicians recognize and treat 4 clinical types of KS (see table below). For this question, relevant one is the treatment highlighted in blue.

From 9
10. No KS treatment thus far directly targets HHV-8.

How is KS associated with HIV?
Initiation of KS is associated with local inflammation, a sign of immune activation. We typically associate full-blown HIV disease, AIDS, with immune suppression. Immune activation and suppression are opposing phenomena. How could the two co-exist as they obviously do in full-blown HIV disease, i.e. AIDS-associated KS?

Immune suppression and inflammation are broad terms we tend to use loosely. Sure full-blown HIV disease, AIDS, has generalized immune suppression but this manifests as deficiency in certain specific, and not all, immune functions. This is why it’s associated with not all and any type of infectious disease but rather with certain specific ones, such as KS, Pneumocystis carinii pneumonia (PCP), tuberculosis (TB), typically infections that remain dormant (latent) in the body and become full-blown diseases with the progression of certain specific immune function deficiencies that accompany untreated or inadequately treated HIV infection. Thus, inappropriate types of immune response, rather than its absence, accompany latency-to-disease progression of many full-blown HIV disease-associated infections.

Effective HIV treatment such as HAART (highly active anti-retroviral therapy) not only restores but also resets general immune function. This in turn reduces local KS-associated inflammation. In addition, HAART contains drugs such as protease inhibitors (PI), which can directly target tumors: (a) by blocking angiogenesis and tumor cell invasion, and (b) tumor cell apoptosis and growth arrest. Thus, rather than AZT effect on KS, it is other drugs such as PI in current HIV HAART Rx that potentially directly target KS. The actual mechanism is subject of ongoing study.

Bibliography

  1. Horwitz, Jerome P., Jonathan Chua, and Michael Noel. “Nucleosides. V. The Monomesylates of 1-(2′-Deoxy-β-D-lyxofuranosyl) thymine1, 2.” The Journal of Organic Chemistry 29.7 (1964): 2076-2078.
  2. Mitsuya, Hiroaki, et al. “3′-Azido-3′-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro.” Proceedings of the National Academy of Sciences 82.20 (1985): 7096-7100.
  3. D’Andrea, Gabriele, Fabrizia Brisdelli, and Argante Bozzi. “AZT: an old drug with new perspectives.” Curr Clin Pharmacol 3.1 (2008): 20-37. Page on researchgate.net
  4. Kaposi, Moriz. “Idiopathic multiple pigmented sarcoma of the skin.” CA: A Cancer Journal for Clinicians 32.6 (1982): 342-347. Idiopathic multiple pigmented sarcoma of the skin
  5. Giraldo, G., E. Beth, and F. Haguenau. “Herpes-type virus particles in tissue culture of Kaposi’s sarcoma from different geographic regions.” Journal of the National Cancer Institute 49.6 (1972): 1509-1526.
  6. Beral, Valerie, et al. “Kaposi’s sarcoma among persons with AIDS: a sexually transmitted infection?.” The Lancet 335.8682 (1990): 123-128. Page on rethinkingaids.com.
  7. Beral, V., et al. “Risk of Kaposi’s sarcoma and sexual practices associated with faecal contact in homosexual or bisexual men with AIDS.” The Lancet 339.8794 (1992): 632-635.
  8. Chang, Yuan, et al. “Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi’s sarcoma.” Science 266.5192 (1994): 1865-1869. Page on pitt.edu
  9. Sgadari, Cecilia, et al. “Pharmacological management of Kaposi’s sarcoma.” Expert opinion on pharmacotherapy 12.11 (2011): 1669-1690. Page on hiv1tat-vaccines.info

Is it true that retrovir can induce immune suppression by inhibiting and also replicating immune cells?

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