Search

Simultaneous measurements of phenotypically defined memory CD4+ cells and in vitro proliferation to three recall antigens (Ags; tetanus toxoid, influenza, and Candida albicans) were performed in 53 HIV-seropositive subjects and 39 HIV-seronegative controls. The results indicate that the low proliferative responses to recall Ags of those who were HIV infected could be partly, but not fully, explained by a decrease of phenotypically defined memory CD4+ cells. This is, to our knowledge, the first report of experiments that simultaneously measured memory CD4+ cell numbers and function and then examined whether the low responses observed in seropositive subjects could be explained by low numbers of phenotypically defined memory CD4+ cells. A central finding of the study, which argues against prevailing dogma, was that within the CD4+ lymphocyte population, the proportion of cells displaying the memory phenotype was not selectively decreased in HIV-seropositive subjects as compared with the proportion of these cells in seronegative homosexual controls. An entirely new finding of the study was that AIDS patients, many of whom were unresponsive to all three recall Ags tested, actually had a significant increase in the proportion of CD4+ cells with the memory phenotype, and this fraction approached 100% in subjects with CD4+ cell numbers that were near zero. A final observation of the study, possible because some patients were on zidovudine (ZDV), was that there was no evidence that ZDV treatment led to an increased proliferative response to recall Ags in vivo. An in vitro study also found no effect of ZDV, dideoxycytidine (ddC), or azido-dideoxyuridine (AZU) on proliferative responses to recall Ags.

HIV infection induces substantial changes in the expression of many lymphocyte phenotypic markers as well as depletion of CD4 lymphocyte numbers. A comprehensive study was undertaken to determine whether seven lymphocyte phenotypic changes associated with HIV infection (increased CD38, HLA-DR, CD57, and CD71 and decreased CD11b, CD45RA, and leu-8) are altered by zidovudine (ZDV) administration. Levels of the four major lymphoid subsets (CD4, CD8, B, and NK cells) and changes in the serum activation markers neopterin and beta 2-microglobulin (beta 2M) were also measured. Elevated pretreatment expression of CD38 and CD71 was reduced significantly toward normal at 2 weeks by ZDV; however, CD38 and CD71 returned to pretreatment levels at different rates. The kinetics of CD38 reduction and the return to pretreatment levels were similar to those of serum neopterin and beta 2M. HLA-DR decreased in many but not all subjects. CD4 lymphocytes showed a transient increase, most evident at 8 weeks of treatment. Lymphoid phenotypes that did not show significant changes after ZDV therapy included CD57, CD11b, CD45RA, and leu-8 markers as well as CD8 T cells, CD20 B cells, and CD56 NK cells. The fact that some lymphocyte phenotypic markers change toward normal with ZDV treatment and others do not indicates that complex processes underlie immune perturbations of HIV infection. Several phenotypic markers (CD38, CD71, and HLA-DR) that are susceptible to short-term effects of ZDV (but with changes that differ from CD4 T cell changes) are surrogate marker candidates for evaluation in anti-HIV treatment.

Sixty-one subjects with mildly symptomatic human immunodeficiency virus (HIV) infection were included in a double-blind, randomized, placebo-controlled trial of zidovudine (part of AIDS Clinical Trials Group protocol 016, ACTG 016) to evaluate changes in the serum immune activation markers neopterin and beta 2-microglobulin (beta 2M) as early markers of the antiviral effect of zidovudine on HIV type 1 (HIV-1) infection. The mean values of serum neopterin and beta 2M levels in 27 placebo-treated subjects tended to increase with time. The mean value of neopterin in 34 subjects receiving zidovudine decreased at 4 weeks (15.76 nmol/L before treatment to 12.73 nmol/L, p = 0.001). The maximum reduction was seen at 8 weeks of treatment (10.78 nmol/L, p less than 0.0001). Subsequently, the mean value of serum neopterin increased but remained below the pretreatment value for more than a year. Serum beta 2M levels decreased (from 3.01 to 2.69 mg/L at 4 weeks, p = 0.01) and reached the lowest level at 8 weeks (2.45 mg/L, p = 0.0002) in zidovudine recipients. The mean beta 2M level returned to pretreatment value at approximately 24 weeks of the treatment. There was a close correlation between changes from baseline in serum neopterin and beta 2M during the first 16 weeks of the zidovudine therapy, but not later. Subjects with greater reductions of serum neopterin or beta 2M tended to maintain lower levels of these markers with continued zidovudine administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Tumor necrosis factor (TNF) has demonstrated antitumor activity against a variety of tumors and is particularly cytotoxic to capillary endothelial cells, which are the presumed cell of origin of Kaposi's sarcoma. We evaluated the toxicity and clinical antitumor and antiretroviral effects of recombinant TNF administered at a once weekly dose of 100 micrograms/m2 intravenously for 8 weeks in five men with AIDS-related Kaposi's sarcoma and without prior opportunistic infection. One patient was removed from study at week 4 due to rapid progression of Kaposi's sarcoma, another patient with stage IV disease and a pretreatment CD4 count of 11 developed fever, hypotension, and pneumonia at week 7 and died 8 days after discontinuing recombinant TNF. No pathogenic organisms were isolated. He had marked eschar formation of his Kaposi's sarcoma lesions, particularly in areas previously exposed to radiation therapy. Uniform toxicities included fevers, rigors, and headaches during drug infusion that were ameliorated by prophylactic meperidine hydrochloride and acetaminophen. All experienced fatigue and three had arthralgias. One patient had transient hypotension which corrected with i.v. fluids. No significant hematologic, hepatic, or renal toxicities were seen. All patients had some progression of their Kaposi's sarcoma on study. There was no change in CD4 or CD8 count or in CD4:CD8 ratios. Serum human immunodeficiency virus (HIV) p24 antigen levels increased greater than 50% in three patients. We conclude that, as a single agent, at a dose of 100 micrograms/m2 recombinant TNF by i.v. infusion has no obvious antitumor or antiretroviral effects in patients with AIDS-related Kaposi's sarcoma.