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More importantly, both gonococcus and chlamydia appear to be important co-factors for HIV transmission. Among African women, for example, gonococcus and chlamydia infections are associated with a fourfold increase in the risk of contracting HIV, and the vaginal secretions of infected HIV-positive women contain an increased amount of virus compared with uninfected HIV-positive women. Recent studies have shown that antibiotic treatment of gonococcal or chlamydial infection dramatically reduces the amount of HIV RNA in semen. In a prospective study, simple syndromic management with antibiotics of minor genital infections, urethritis, and genital ulcer syndrome dramatically decreased HIV transmission.

Gonococcus is developing resistance to antibiotics, however. Clinicians have already lost penicillin and tetracycline, which were the drugs of choice until about 2 years ago. Isolated cases of resistance to ciprofloxacin and chlorinated quinoline have appeared in the United States and will probably spread. If clinicians lose the second- and third-generation cephalosporins, treatment would becomes a very significant problem.

Natural Immunity. Like Helicobacter pylori, there is little or no naturally acquired immunity to gonococcus. Infections persist, and reinfections are common. Nevertheless, there are convincing data from the era before antibiotics indicating that a deep and persistent gonococcal infection resulted in an immunological cure. In fact, there are a few articles in the old literature on the use of therapeutic vaccines. Despite the shortcomings of these studies, they do suggest that gonococcus, however elegantly it evades the immune response, cannot completely evade a truly vigorous response, and that this effective immune response could be utilized in a vaccine.

This relative lack of a protective immune response to uncomplicated genital infection is surprising, at first glance, because such infection does result in a very vigorous systemic and mucosal antibody response against a number of gonococcal antigens. The mechanisms by which gonococci escape what might otherwise be an effective immune response include rapid antigenic variation of key surface proteins, masking of surface antigens by sialylation of gonococcal lipooligosaccharide (LOS), production of IgA protease, and stimulation of “blocking” antibodies.

In part because of the lack of a good animal model in which to study immune response, past research has focused on the genetics, molecular biology, and pathophysiology of gonococcus rather than functional or protective immune responses. Researchers have learned a good bit about several of these gonococcal antigens, and this knowledge may provide explanations for the lack of natural immunity, as well as candidate antigens that might become the basis for gonococcal vaccines.

Current Candidate Antigens. Most of the initial research concentrated on different forms of gonococcal pilus, a surface appendate that functions as an adherence ligand, and its main subunit (pilin). Antibodies to pilus block adherence and opsonize phagocytes, but gonococci generate a bewildering antigenic variation in pilus. In a human volunteer study, a pilus subunit vaccine adminis-



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