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Posted: 27 May 2011
30 years in 30 weeks, 1986

In 1986 the International Committee on the Taxonomy of Viruses ruled that the AIDS-causing virus would be called Human Immunodeficiency Virus, ending the argument between the French and American groups, who wanted to call the virus LAV and HTLV-III, respectively. The year also saw the first clinical trial of AZT, although the paper describing the trial was published only in 1987. The trial was stopped early due to the clear reduction in mortality in the drug arm as compared to the placebo group. Meanwhile, basic researchers continued to uncover further properties of the virus that made it so unique. The destruction of CD4 T cells in AIDS patients was observed in the very first report published in 1981, but in 1986 the paper by Robin Weiss and co-authors featured in this week's 30 years in 30 weeks showed that HIV uses the CD4 molecule itself as a receptor to enter lymphocytes and cells in brain.

The T4 gene encodes the AIDS virus receptor and is expressed in the immune system and the brain.
Cell. 1986 Nov 7;47(3):333-48.
Maddon PJ, Dalgleish AG, McDougal JS, Clapham PR, Weiss RA, Axel R.

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Commentary by Dr. Robin Weiss

The discovery that CD4 is the receptor to which HIV attaches on susceptible cells followed not long after the discovery of HIV itself. From the first proper clinical description of HIV in 1981 (see Gottlieb, this series) it became clear that AIDS resulted from a selective loss of helper T-lymphocytes bearing the CD4 cell surface antigen (or T4 as it was then commonly called). After the isolation of HIV-1 in Paris in 1983 (see Barré-Sinoussi, this series), David Klatzmann and Luc Montagnier showed that HIV infected CD4 cells but not CD8 T-cells in vitro. However, it was not at all obvious that HIV would use the very same cell surface molecule that immunologists used to type T cells. We therefore sought to identify the HIV receptor by screening all the cell surface molecules known at that time to be expressed on T cells. Over 150 monoclonal antibodies (mAbs) specific to these various proteins had been collected by Peter Beverley. Therefore, his laboratory and mine combined forces and Gus Dalgleish found that only antibodies binding to CD4 blocked HIV infection. Klatzmann had come to a similar conclusion, and our papers were published together in December 1984 in Nature. In 1986, we acquired a larger set of anti-CD4 antibodies and Quentin Sattentau showed in Science that only antibodies binding to the first or second globular domains on the CD4 antigen blocked HIV entry.

In 1985, the cDNA encoding the CD4 protein was cloned by Dan Littman in Richard Axel’s laboratory at Columbia University. I vividly recall receiving a telephone call from Richard (no e-mails in those days!) suggesting we should collaborate on testing whether expression of the CD4 gene would confer susceptibility to HIV infection to CD4-negative cells. Paul Maddon in Axel’s laboratory prepared HeLa cells and B cells expressing CD4, and we found that we could infect them with HIV whereas control cells were resistant. This clear cut finding confirmed that CD4 really was the HIV receptor.

We then tested whether mouse cells expressing human CD4 were susceptible to HIV, because the construction of mice transgenic for human CD4 might provide a small animal model for investigating AIDS. However, in this case we could not detect infection. In addition, ‘pseudotype’ of vesicular stomatitis virus (VSV) bearing HIV envelope glycoproteins was also unable to infect murine cells bearing human CD4. VSV is not subject to intracellular restriction factors like HIV, and it will readily propagate in mouse cells provided it can gain entry, so this experiment told us that CD4 was necessary but not sufficient for HIV infection. An additional factor specific to humans was needed for HIV entry.

It took a further ten years before the missing factors or coreceptors, CXCR4 and CCR5, were discovered by Ed Berger at the NIH. Protein crystallography and site-specific mutagenesis confirmed the high affinity binding of HIV gp120 to CD4 and helped to elucidate the conformational changes that occur following binding of virus to CD4, which allows the virus to interact with coreceptors, and leads to fusion of the virus envelope and the cell membrane. In the meantime, recombinant soluble CD4 proteins were found to be potent inhibitors of laboratory-adapted strains of HIV, but were relatively weak in inhibiting primary, CCR5-dependent strains. In fact, while drugs that stop HIV interaction with CCR5 have found a place in the clinic, blocking attachment of HIV to CD4 by small molecular weight compounds has been less successful.

The CD4 antigen continues to be a valuable predictor of whether HIV-infected patients will progress to AIDS. Several of the antibodies binding to the region of gp120 that interacts with CD4 can potently neutralize HIV and they are being exploited in vaccine design.

About the author: Robin Weiss is Professor of Viral Oncology at University College London.

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