Natural properties of the immune system play an important role in HIV infection and its course, including long-term non-progressors (LT-NPs), a topic explored in Session A12 on chemokines and their receptors. Jay Levy, of the University of California, San Francisco, introduced the session on a non-chemokine note. His discovery several years ago that CD8 cells produce a factor (CAF) that blocks HIV infection was one stimulus to the discovery that chemokine receptors CCR5 and CXCR4 are co-receptors for HIV infection. Production of CAF is strong in healthy persons and lost during disease progression, but remains strong in LT-NPs. CAF has proved difficult to isolate because it is present in such low quantities. "Factors have a ten-year life," Levy said. "We have two more years." Some have suggested that chemokines might be used clinically to block HIV infection. But, Levy said, "I question whether they'll be of any use in therapy."

Co-receptors CCR5 and CXCR4 influence which host cells a strain of HIV favours. Heterosexual transmission, which accounts for an increasing proportion of new infections among women, most often involves CCR5 virus. Julie McElrath, of the University of Washington, asked whether this could be due to the type of co-receptors predominantly found in immune cells of the female genital tract. She reported that HIV infects lymphocytes, which express both co-receptors, but does not replicate in them, while the opposite situation occurs with dendritic cells, which express mostly CXCR4. Productive replication of HIV requires "stable conjugates" of lymphocytes and dendritic cells, she discovered. These cell couples occur naturally in the genital mucosa. "Co-receptor expression alone cannot account for preferential [heterosexual] transmission of CCR-5 strains," Dr. McElrath concluded.

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After infection occurs, genetic factors help determine its natural course, according to Magdalena Magierowska, of the French ALT and IMMUNOCO Study Groups. She compared the frequency of deletions in the genes for three co-receptors between rapid progressors and LT-NPs, as well as the frequency of several HLA alleles. The deletion CCR5D 32 occurred significantly more often in LT-NP, she found, as did characteristic HLA allele patterns, such as B27-positive and DR6-negative. "Host genetic background plays an important role in evolution of HIV disease," Magierowska concluded. Its predictive value for LT-NP was 66%, "still a long way from 100%,"she acknowledged.

In Session A13, Kuan-Teh Jaeng, of the US NIAID, investigated why heterozygotes – persons carrying one normal CCD5 gene and one D 32 allele – are relatively resistant to HIV infection. There has been "a flurry of excitement" about biological resistance to HIV infection, he said, some of which is due to the D 32 variant. But why are persons with one good copy of CCR% partially resistant? "How does the bad copy of the gene interfere with the good copy?" Jaeng wondered. He found that, in heterozygotes, CCR5 protein doesn’t reach the cell membrane. It is trapped inside the cell, bound to copies of D 32 protein. This shows that co-receptor proteins form multimers, or "shake hands with each other," as Jaeng explained. His finding suggests that reducing the amount of CCR5 should interfere strongly with its receptor activity.

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