virology blog

About viruses and viral disease

antiretroviral

The Berlin patient

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HIV binding CD4 and ccrSince the beginning of the AIDS epidemic, an estimated 75 million people have been infected with HIV. Only one person, Timothy Ray Brown, has ever been cured of infection.

Brown was diagnosed with HIV while living in Berlin in 1995, and was treated with anti-retroviral drugs for more than ten years. In 2007 he was diagnosed with acute myeloid leukemia. When the disease did not respond to chemotherapy, Brown underwent stem cell transplantation, which involves treatment with cytotoxic drugs and whole-body irradiation to destroy leukemic and immune cells, followed by administration of donor stem cells to restore the immune system. When his leukemia relapsed, Brown was subjected to a second stem cell transplant.

The entry of HIV-1 into lymphocytes requires two cellular proteins, the receptor CD4, and a co-receptor, either CXCR4 or CCR5. Individuals who carry a mutation in the gene encoding CCR5, called delta 32, are resistant to HIV-1 infection. This information prompted Brown’s Berlin physician to screen 62 individuals to identify a stem cell donor who carried a homozygous CCR5∆32 mutation. Peripheral blood stem cells from the same donor were used for both transplants. 

Despite enduring complications and undergoing two transplants, Brown’s treatment was a success: he was cured both of his leukemia and HIV infection. Even though he had stopped taking antiviral drugs, there was no evidence of the virus in his blood following his treatment, and his immune system gradually recovered. Follow-up studies in 2011, including biopsies from his brain, intestine, and other organs, showed no signs of HIV RNA or DNA, and also provided evidence for the replacement of long-lived host tissue cells with donor-derived cells. Today Brown remains HIV-1 free.

Although Brown’s cure is somewhat of a medical miracle, and by no means a practical road map for treating AIDS, the example of the Berlin patient has galvanized research efforts and continues to inspire hope that a simpler and more general cure for infection may someday be achieved. Clinical trials have been conducted to test a variety of strategies in which CD4+ T or stem cells are obtained from a patient, the CCR5 gene is either mutated or its translation blocked by RNA interference, and then the resulting virus-resistant cells are returned to the patient. In one case zinc finger nucleases were used to delete the CCR5 gene in a patient’s cells, a procedure that we discussed in TWiV #278.

AZT inhibits XMRV

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aztXenotropic murine leukemia virus related virus (XMRV) has been implicated in prostate cancer and chronic fatigue syndrome (CFS). Because XMRV is a retrovirus, it has been suggested that it might be susceptible to some of the many drugs available for treatment of AIDS. Of ten licensed compounds evaluated for activity against XMRV, just one, AZT (azidothymidine), was found to inhibit viral replication.

Compounds used to treat HIV-1 infection fall into distinct classes: protease inhibitors (Ritonavir, Saquinavir, or Indinavir), nucleoside reverse transcriptase inhibitors (NRTI, AZT, 3TC, Tenofovir, D4T), non-nucleoside reverse transcriptase inhibitors (NNRTI, Efavirenz, Nevirapine), integrase inhibitors (118-D-24), and fusion inhibitors (Maraviroc). None of the HIV-1 protease inhibitors, NNRTI, or integrase inhibitors blocked XMRV replication.  Of the NRTIs, only AZT significantly inhibited viral replication. Fusion inhibitors were not examined in this study.

AZT was the first drug licensed to treat AIDS. It is phosphorylated to the active form by cellular enzymes. Phosphorylated AZT is an inhibitor of viral reverse transcriptase because it acts as a chain terminator when incorporated into DNA:

azt_mechanism

Because AZT has a N3 (azido) group on the ribose instead of a hydrogen, the next base cannot be added to the DNA chain and synthesis stops.

The relative selectivity of this drug depends on the fact that reverse transcription takes place in the cytoplasm, where the drug appears first and in the highest concentration. But the presence of AZT monophosphate causes depletion of the intracellular pool of ribosylthymine 5′-triphosphate (TTP). Therefore AZT has substantial side effects which include muscle wasting, nausea, and severe headaches. AZT treatment can also damage bone marrow, which requires multiple transfusions of red blood cells. The drug was used extensively because there was no alternative until other antivirals were developed.

AZT can be taken orally but it is degraded rapidly by liver enzymes. Patients must take the drug two or three times a day to maintain an effective antiviral concentration. The drug is modestly effective in infected adults, leading to a transient increase in CD4+ T-cell counts.

Much effort has been devoted to discovering alternatives to AZT, and several nucleoside analogs that have therapeutic value, such as 3TC, are available. However 3TC does not inhibit XMRV replication.

It is not known if treatment with AZT will effect either prostate cancer or CFS. If prostate cancer is triggered when XMRV inserts into chromosomal DNA, then the drug will not likely block progression of the disease because the drug does not eliminate infected cells. Whether reduction of viral loads by AZT treatment has a positive therapeutic outcome remains to be determined. Because AZT is approved for use in humans, such studies can proceed immediately, without the need for extensive toxicity studies in animals.

Sakuma R, Sakuma T, Ohmine S, Silverman RH, & Ikeda Y (2009). Xenotropic murine leukemia virus-related virus is susceptible to AZT. Virology PMID: 19959199