Within-patient HIV evolution reflects the strong selection pressure driving viral escape from cytotoxic T-lymphocyte (CTL) recognition. Whether this intrapatient accumulation of escape mutations translates into HIV evolution at the population level has not been evaluated. We studied over 300 patients drawn from the B- and C-clade epidemics, focusing on human leukocyte antigen (HLA) alleles HLA-B57 and HLA-B5801, which are associated with long-term HIV control and are therefore likely to exert strong selection pressure on the virus. The CTL response dominating acute infection in HLA-B57/5801-positive subjects drove positive selection of an escape mutation that reverted to wild-type after transmission to HLA-B57/5801-negative individuals. A second escape mutation within the epitope, by contrast, was maintained after transmission. These data show that the process of accumulation of escape mutations within HIV is not inevitable. Complex epitope- and residue-specific selection forces, including CTL-mediated positive selection pressure and virus-mediated purifying selection, operate in tandem to shape HIV evolution at the population level.

We describe a gonorrhoea case with combined high-level azithromycin resistance and ceftriaxone resistance. In February 2018, a heterosexual male was diagnosed with gonorrhoea in the United Kingdom following sexual intercourse with a locally resident female in Thailand and failed treatment with ceftriaxone plus doxycycline and subsequently spectinomycin. Resistance arose from two mechanisms combining for the first time in a genetic background similar to a commonly circulating strain. Urgent action is essential to prevent further spread.

Most asymptomatic individuals infected with HIV-1 have a cytotoxic T lymphocyte (CTL) response to the virus Gag proteins which can be demonstrated in vitro. Epitopes have been mapped in p17 Gag and p24 Gag restricted by HLA-B8 (p17-3 and p24-13) and -B27 (p24-14). Viruses isolated from patients who make CTL responses to these peptides vary within the genetic sequences encoding these epitopes and some mutations lead to reduction in killing activity in vitro. This was attributed to either failure of the variant epitope to bind major histocompatibility complex class I or failure of T-cell receptors to bind the presented peptide. But peptide variants of class I-restricted epitopes cause 'antagonism', that is, the presence of a variant epitope (in the form of peptide) inhibits normal lysis of targets presenting the original epitope. This mirrors similar findings in class II-restricted systems. Here we report that naturally occurring variant forms of p17-3, p24-13 and p24-14 may cause antagonism of CTL lines derived from the same individuals. The effect is present if the epitopes are derived from synthetic peptides and when they are processed from full-length proteins expressed by either recombinant vaccinia constructs or replicating HIV.

The precise role played by HIV-specific cytotoxic T lymphocytes (CTL) in HIV infection remains controversial. Despite strong CTL responses being generated during the asymptomatic phase, the virus persists and AIDS ultimately develops. It has been argued that the virus is so variable, and the virus turnover so great that escape from CTL recognition would occur continually, but so far there is limited evidence for CTL escape. The opposing argument is that evidence for CTL escape is present but hard to find because multiple anti-HIV immune responses are acting simultaneously during the asymptomatic phase of infection. We describe six donors who make a strong CTL response to an immunodominant HLA-B27-restricted epitope. In the two donors who progressed to AIDS, CTL escape to fixation by the same mutation was observed, but only after 9-12 years of epitope stability. CTL escape may play an important role in the pathogenesis of HIV infection.

Human immunodeficiency virus (HIV)-1 amino acid sequence polymorphisms associated with expression of specific human histocompatibility leukocyte antigen (HLA) class I alleles suggest sites of cytotoxic T lymphocyte (CTL)-mediated selection pressure and immune escape. The associations most frequently observed are between expression of an HLA class I molecule and variation from the consensus sequence. However, a substantial number of sites have been identified in which particular HLA class I allele expression is associated with preservation of the consensus sequence. The mechanism behind this is so far unexplained. The current studies, focusing on two examples of “negatively associated” or apparently preserved epitopes, suggest an explanation for this phenomenon: negative associations can arise as a result of positive selection of an escape mutation, which is stable on transmission and therefore accumulates in the population to the point at which it defines the consensus sequence. Such negative associations may only be in evidence transiently, because the statistical power to detect them diminishes as the mutations accumulate. If an escape variant reaches fixation in the population, the epitope will be lost as a potential target to the immune system. These data help to explain how HIV is evolving at a population level. Understanding the direction of HIV evolution has important implications for vaccine development.

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Previous studies have shown that smoking i s associated with a high incidence of certain malignancies and a high incidence of metastatic spread of melanoma. The purpose of the present study was t o examine whether this high incidence of malignancy could be associated with certain aspects of immune function believed to be important in restricting tumour growth. Age-and sex-matched smoking and non-smoking normal subjects and male, smoking and non-smoking melanoma patients, were studied for the natural killing (NK) activity of their blood leukocytes against cultured melanoma and Chang cells. The levels of the various immunoglobulin classes in their sera and the E rosette levels of the normal subjects were also assessed. The results indicate that the N K activity of blood leukocytes from both normal subjects and melanoma patients who smoked was significantly lower against cultured melanoma cells than that of non-smokers. Smokers were also shown t o have lower IgG and IgA immunoglobulin levels i n their sera compared t o nonsmokers but no differences i n the percentage of E-rosetting (T) cells was detected. Recent studies provide some basis for the belief that the low N K activity and immunoglobulin levels i n smokers may be related. These results further suggest that a closer examination of the effects of this environmental hazard on the immune system and i t s relation t o malignancy i s needed.It is well known that smoking is associated with a raised incidence of a variety of malignant diseases such as carcinoma of the lung, oesophagus and bladder (Doll and Peto, 1976). It has also been shown that there is a higher incidence of metastatic disease, after 5 years, in male patients with malignant melanomas who smoke, than in those who are nonsmokers (Shaw et al., 1979). The underlying cause for this association between smoking and the increased incidence of malignancy is unknown and it is probable that multiple factors may be involved, including direct carcinogenic effects of products formed from tobacco during smoking.One of the possible associations, however, that has received little attention, is that related to the effects of smoking on the immune system. There is much experimental evidence from studies on both man and animals to show that smoking causes changes in the immune system (Holt and Keast, 1977) and surveillance by the immune system is considered important in control of tumour emergence and growth.In particular, recent studies have suggested that natural killer (NK) activity may play an important role in tumour surveillance (Kiessling and Haller, 1978; Baldwin, 1977; Hersey, 1979). Research originating in this laboratory has provided additional support for a surveillance role for NK cells in that melanoma patients with low post-operative NK activity against melanoma target cells had a significantly higher incidence of recurrence of melanoma than did patients with higher post-operative NK activity (Hersey et al., 1978).The present study was undertaken to determine whether an association between smoking a...

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