Sharing the spotlight in Durban: A report from IAS TB2016 at AIDS2016.

Tuberculosis (TB) is now recognized as the number one cause of death worldwide due to a single infectious pathogen and is the cause of death in one-third of people living with HIV worldwide. An inaugural pre-conference focused on TB (TB2016) was held at the International AIDS Society Conference AIDS2016. This report focuses on key messages from the TB2016 conference that are important for the medical, public health, activist, and scientific communities.

Pathogenicity of glycoprotein C negative mutants of herpes simplex virus type 1 for the mouse central nervous system.

A previous study from our laboratory showed that a mutant of herpes simplex virus type 1 (HSV-1), strain KOS-321, carrying a deletion in the structural gene for glycoprotein C (gC) had reduced pathogenicity for the mouse central nervous system when compared to the wild-type virus (Kümel et al., 1985). In this study, eight additional gC negative (gC-) mutants derived from KOS-321 were shown to vary widely in their ability to induce lethal encephalitis in female DBA/2 mice following intracerebral inoculation. This variation in virulence showed no correlation with thymidine kinase activity. One less virulent gC- strain, gC-39, was further studied to determine whether the neurovirulent phenotype could be restored by rescue of the gC gene using standard marker rescue cotransfection procedures. The resulting progeny contained 2% gC+ recombinant virions and was tested for its ability to cause encephalitis. Although this progeny had increased virulence, it was not attributable to the acquisition of the gC gene since passive immunization of mice with a pool of anti-gC monoclonal antibodies had no effect on the development of encephalitis and only gC- viruses were isolated from diseased brain tissues. In agreement with these findings, individual plaque-purified gC positive (gC+) virus recombinants were shown not to have been restored to the wild-type virus level of neurovirulence. It is concluded that gC is not a virulence determinant in this mouse model of HSV-induced encephalitis and that cotransfection procedures can induce additional mutations that affect viral pathogenesis.

Enhanced efficacy of nucleoside analogs and recombinant alpha interferon in weanling mice lethally infected with herpes simplex virus type 2.

Weanling ICR Swiss mice were inoculated intranasally with a lethal dose of herpes simplex virus type 2, and treated with either vidarabine, vidarabine-5'-monophosphate, acyclovir or a hybrid recombinant human alpha interferon which is active in murine tissues. Treatment with antiviral drugs was initiated 2, 24, 48, 72 or 96 h following virus inoculation. Single drug treatment showed little effect on mortality, with only acyclovir showing some slight reduction. Four dual drug combinations (vidarabine/acyclovir; vidarabine/interferon; vidarabine 5'-monophosphate/acyclovir and vidarabine 5'-monophosphate/interferon) were all associated with marked reductions of mortality when treatment was begun at 2 h, and this beneficial effect increased further when therapy was delayed until 24 or 48 h following virus inoculation. However, the combination of acyclovir/interferon was consistently toxic to the mice, unless a reduction in dosages was employed. These results suggest that certain antiviral combinations might be useful for serious human infections caused by herpes simplex virus.

Probable autochthonous Plasmodium vivax malaria transmission in Michigan: case report and epidemiological investigation.

In September 1995, a Michigan resident with no history of international travel was diagnosed with Plasmodium vivax infection, and local mosquito-borne transmission was suspected. An epidemiological investigation did not identify additional cases of local transmission, and there was no apparent link to the 12 imported malaria cases detected in the region. Potential sites of nighttime outdoor exposure included a campground in a swampy area, close to a racetrack frequented by international travelers, some of whom were known to come from countries with malaria transmission. Entomological investigation identified Anopheles spp. larvae and adults near the campsite. Summer temperatures 4.2 degrees C above average would have contributed to shortened maturation time of P. vivax within the insect vector, increasing the likelihood of infectivity. These investigations indicated that this patient probably acquired P. vivax infection through the bite of a locally infected Anopheles spp. mosquito. Physicians need to consider malaria as a possible cause of unexplained febrile illness, even in the absence of international travel, particularly during the summer months.

Rhodococcus equi infection in patients with and without human immunodeficiency virus infection.

Rhodococcus equi is an uncommon pathogen in humans that has occasionally been reported to cause infection in individuals with impaired cellular immunity. We summarize 30 previously published reports of human infection with R. equi and describe one additional case in a patient with AIDS. Eleven (35%) of the patients discussed in this report had AIDS or human immunodeficiency virus (HIV) infection, which is emerging as the leading cause of immunosuppression in cases of R. equi infection. Seventy-seven percent of all patients had pneumonia due to R. equi, and the infiltrate frequently cavitated. When HIV-infected patients were compared with those not infected with the virus, symptoms, age, and frequency of pneumonia were similar. Sputum and blood cultures were more likely to be positive in HIV-infected patients. Individuals with HIV infection also had a higher incidence of simultaneous secondary infections and higher mortality than non-HIV-infected patients (54.5% vs. 20%). The rate of survival for all patients was 75% when antibiotics were combined with surgical resection of infected tissue; in comparison, the survival rate among patients receiving antibiotics alone was 61.1%.

Characterization of encephalitis in adult mice induced by intracerebral inoculation of herpes simplex virus type 1 (KOS) and comparison with mutants showing decreased virulence.

The spread of herpes simplex virus type 1 (HSV-1) strain KOS, and two less neurovirulent mutants of the strain was studied in female DBA/2 mice during the 1- to 5-day postinoculation period after intracerebral inoculation. Immunohistopathology showed that wild-type KOS virus first infected the meninges and ependymal cells but did not infect cells at the inoculation sites. The virus continued to spread to some cells directly adjacent to ventricles; however, the most extensive and severe lesions were found in the pyriform lobes and other structures associated with the limbic system. The pattern of spread suggested that direct cell to cell viral spread is important but that retrograde axonal transport to distant sites probably accounts for the more severe lesions associated with the limbic system. Both less neurovirulent mutant viruses multiplied to a much lesser degree in the brain and spread less extensively than the wild type virus when equivalent doses were given; however, when a large dose of the least neurovirulent mar C10.1 mutant virus was inoculated, infection spread rapidly to the same regions of the brain affected by KOS. Studies of mar C10.1 showed that thymidine kinase deficiency, rather than a mutation in the gene coding for glycoprotein C, probably accounted for the decreased neurovirulence of this mutant. This mouse model of HSV-1 virus-induced encephalitis, in combination with appropriate studies of the molecular biology of the HSV-1 KOS strain, should be useful for the study of neurovirulence factors contributing to the pathogenesis of HSV-1.

Comparative activities of selected combinations of acyclovir, vidarabine, arabinosyl hypoxanthine, interferon, and polyriboinosinic acid-polyribocytidylic acid complex against herpes simplex virus type 2 in tissue culture and intravaginally inoculated mice.

The effects of double and triple combinations of acyclovir (ACV), adenine arabinoside (ara-A), arabinosyl hypoxanthine, or interferon on herpes simplex virus type 2 in mouse embryo fibroblasts were measured. These in vitro data were compared with results obtained in mice infected intravaginally with herpes simplex virus type 2 and treated intraperitoneally with low- and high-dose combinations of ACV, ara-A, or polyriboinosinic-polyribocytidylic acid(poly-L-lysine)carboxymethylcellulose complex [poly IC(LC)], an interferon inducer. Although all double combinations and one triple combination evoked synergistic reactions in vitro, results did not necessarily predict in vivo observations. In vivo synergy was observed when combinations of ACV and ara-A and low doses of ara-A-ACV-poly IC(LC) were used. However, toxicity was seen with full-dose nucleoside-poly IC(LC) doublets. The full-dose ACV-ara-A combination completely prevented progression beyond vaginitis, with all animals surviving. The ara-A-ACV results observed in mice, together with in vivo data of others, suggest that this combination might prove clinically useful for certain herpes simplex virus type 2 infections.