Increase of the production of tumor necrosis factor in endotoxin shock in mice presensitized with sera of tumor-bearing mice or tumor cell factor]

We investigated the phenomenon of increased sensitivity of tumor-bearing mice to endotoxin shock. I/V administration of sera from tumor (EL-4, B16, R815, MOPC-315) bearers or tumoral culture media into intact mice caused the increased sensitivity to lethal action of LPS plus GMDP. Production of TNF in above mice was also significantly increased under the influence of LPS plus GMDP. Sensitivity induced factors in tumor bearing mice sera have mol. weight more than 50 kDa. This action was partially abolished by indomethacin.     

Search for the Mechanism of Genetic Variation in the pro Gene of Human Immunodeficiency Virus

To study the mechanism of evolution of the human immunodeficiency virus (HIV) protease gene (pro), we analyzed a database of 213 pro sequences isolated from 11 HIV type 1-infected patients who had not been treated with protease inhibitors. Variation in pro is restricted to rare variable bases which are highly diverse and differ in location among individuals; an average variable base appears in about 16% of individuals. The average intrapatient distance per individual variable site, 27%, is similar for synonymous and nonsynonymous sites, although synonymous sites are twice as abundant. The latter observation excludes selection for diversity as an important, permanently acting factor in the evolution of pro and leaves purifying selection as the only kind of selection. Based on this, we developed a model of evolution, both within individuals and along the transmission chain, which explains variable sites as slightly deleterious mutants slowly reverting to the better-fit variant during individual infection. In the case of a single-source transmission, genetic bottlenecks at the moment of transmission effectively suppress selection, allowing mutants to accumulate along the transmission chain to high levels. However, even very rare coinfections from independent sources are, as we show, able to counteract the bottleneck effect. Therefore, there are two possible explanations for the high mutant frequency. First, the frequency of coinfection in the natural host population may be quite low. Alternatively, a strong variation of the best-adapted sequence between individuals could be caused by a combination of an immune response present in early infection and coselection.     

Model with two types of CTL regulation and experiments on CTL dynamics

Recently, we developed a mathematical model of interaction between the HIV and the immune system to match various dynamic experiments carried out in HIV-infected humans and SIV-infected macaques. The model includes helper cell-dependent and helper cell-independent cytotoxic lymphocytes (CTLs) and predicts two stable steady states, a state with a high virus load and few helper cells, and another state with a low virus load and many helper cells. Here we upgrade the model to take into account recent reports on the link between the activation status of infected cells and their ability to produce virus, the effect of helper cells at the time of priming on CTL differentiation, and virus dynamics in unvaccinated macaques with a broad genetic background acutely infected with SIVmac251. We also discuss in detail the experimental justification of the CTL block and the robustness of model predictions with respect to the hypothesis of two CTL subtypes.