Linda Morfeldt-Månson

Temporal fluctuations in HIV quasispecies in vivo are not reflected by sequential HIV isolations

A genetic study has been made of the HIV tat gene from sequential HIV-1 isolates and the corresponding infected peripheral blood mononuclear cells. DNA was amplified by polymerase chain reaction (PCR) and cloned into a eukaryotic expression vector. Twenty clones were sequenced from each sample. Comparing the sequential HIV isolates, abrupt differences were seen between the major forms of each isolate. These progressive changes were not reflected at all among the in vitro samples. The fluctuation in the quasispecies in vivo may suggest a much more dynamic role for latently infected mononuclear cells. High frequencies of functionally defective tat genes were identified. Given such complexity and the evident differences between quasispecies in vivo and in vitro, the task of defining HIV infection in molecular terms will be difficult.

REPLICATIVE CAPACITY OF HUMAN IMMUNODEFICIENCY VIRUS FROM PATIENTS WITH VARYING SEVERITY OF HIV INFECTION

T-lymphotropic viruses were isolated from 31 patients with different clinical manifestations of human immunodeficiency virus (HIV) infection. Lymphocyte cultures from patients with the acquired immunodeficiency syndrome (AIDS) or pre-AIDS yielded virus rapidly, as indicated by high levels of reverse transcriptase (RT) activity in culture fluids. These viruses were able to establish a persistent infection in several T4-antigen-positive tumour cell-lines. In contrast, lymphocyte cultures from patients with mild or no symptoms yielded virus more slowly and the RT activity was low. Co-cultivation of slow/low-yielding lymphocytes with T4-positive tumour cell-lines showed no or only transient virus production. In 14 out of 23 cases virus could be detected by their fatal cytopathic effects on tumour cells. The relation between severity of illness and in-vitro replication potential of the viruses suggests that in the course of an infection selection may occur for HIV variants that replicate efficiently in T4 cells.

Oral candida albicans in HIV infection.

The prevalence of oral colonization with Candida albicans was studied in 225 homosexual men, 99 of whom had HIV antibodies and in 175 heterosexual men. Oral candidal carriage was most prevalent among HIV seropositive homosexual men (77.8%). Rich growth of C. albicans in culture and findings of pseudomycelial elements in oral mucosal smear also correlated with HIV seropositivity. Pseudomycelial forms of C. albicans were demonstrated in mucosal smear from all patients with oral mucosal lesions suspected for candidiasis. However, 26/53 patients (49.1%) with positive smear had no clinical signs of oral candidiasis. The oral yeast flora was sampled twice in 85 homosexual men at an interval of 12-18 months. 71/85 patients (83.5%) were grouped into the same category of candidal colonization; carrier or noncarrier state, on both occasions. No statistically significant differences in numbers of CD 4 cells or CD 8 cells were observed between patients with respect to candidal colonization, when HIV seropositive and seronegative homosexual men were considered separately.

Isolate-specific neutralizing antibodies in patients with progressive HIV-1-related disease.

Four individuals with increasing severity of HIV-1 infection were studied for serum neutralizing activity against their own virus isolates collected during 1-3 years. Sequential serum samples and HIV-1 isolates were available from these patients from the stage of lymphadenopathy to severe immunodeficiency. The replicative capacity of isolates changed from slow/low to rapid/high in each patient during the study period. Sequential virus isolates showed differences in sensitivity to neutralization by autologous as well heterologous area. Taken together with our previous results demonstrating that variant viruses resistant to neutralization by autologous sera emerge during the year following primary infection, neutralization-resistant variants seem to emerge during the entire course of HIV-1 infection. The ability to produce neutralizing antibodies to autologous virus appears to correlate with replicative capacity of the virus and the degree of immunodeficiency in the patient.

Clinical signs and laboratory markers in predicting progression to AIDS in HIV–1 infected patients

In a prospective longitudinal study 89 men with HIV-1 infection were observed for a mean time of 51 months with regard to clinical signs and laboratory findings predictive of progression to AIDS/opportunistic infection (OI). In a bivariate regression analysis the clinical signs showing a significant relation to AIDS development were: dermatitis of the face, yellow toe nail changes, hairly leukoplakia and oral candidiasis. The laboratory findings significantly associated with progression to AIDS were: decrease of the relative and absolute number of CD4 lymphocytes, decrease of the CD4/CD8 ratio, HIV p24 antigenaemia, lack of anti-HIV p24, elevated erythrocyte sedimentation rate, anaemia and elevated serum-beta-2-microglobulin. The relative number (%) of CD4 cells was found superior to the absolute number and the CD4/CD8 ratio. In a multivariate regression analysis decrease of CD4 lymphocytes and lack of anti-HIV p24 were independently associated with subsequent AIDS/OI development.

Dermatitis of the Face, Yellow Toe Nail Changes, Hairy Leukoplakia and Oral Candidiasis Are Clinical Indicators of Progression to AIDS/Opportunistic Infection in Patients with HIV Infection

In a prospective longitudinal study of 89 men with HIV infection and persistent generalized lymphadenopathy (PGL) we tried to find clinical signs predictive of development to AIDS/opportunistic infection (OI). The mean observation time was 47 months. 27 patients (30%) developed AIDS/OI after a mean of 37 months. The estimated median time from diagnosis of PGL to AIDS/OI was 68 months. Four clinical signs of progression towards AIDS/OI were identified: dermatitis of the face, yellow toe nail changes, hairy leukoplakia and oral candidiasis. One or more of these signs were recorded in 25/27 (93%) of the patients before the development of AIDS/OI. The estimated median time from registration of each sign to AIDS/OI was: dermatitis of the face, 29 months; yellow toe nail changes, 21 months; hairy leukoplakia, 18 months; and oral candidiasis, 10 months. The estimated median time from herpes zoster to AIDS was only slightly shorter than the estimated time from diagnosis of PGL to AIDS/OI.

A prospective study of 115 initially asymptomatic HIV infected gay men in Stockholm, Sweden.

A cohort of 115 asymptomatic gay men, all seropositive for HIV, was recruited in a health screening project in Stockholm, Sweden, between Nov. 1982 and Dec. 1983 and subsequently followed and clinically evaluated after a mean observation time of 63 months. AIDS in accordance with the surveillance definition (CDC group IV C-1 and D) developed in 34 (29.6%) of the men, while 1 (0.9%) additional man died of multiple myeloma classified as CDC group IV E. Constitutional symptoms (CDC group IV A) developed in 13 (11.3%) men, while symptoms from the central nervous system classified as CDC group IV B occurred in 1 (0.9%) additional man. Minor opportunistic infections included in the definition for CDC group IV C-2 developed in 12 (10.4%) men, while 48 (41.7%) men remained asymptomatic, with or without persistent generalized lymphadenopathy (PGL). One man who died of AIDS had been treated for malignant melanoma (MM) and one who did not fulfill the criteria for CDC group IV died of MM during the observation period. The 5-year actuarial progression rate to surveillance defined AIDS was 31.5% and to CDC group IV 53.6%. No statistically significant association was found between disease progression and a number of recorded epidemiological variables, most previous and present sexually transmitted diseases (STD) (except gonorrhoea) and the presence of PGL at entry. On the other hand, reduced delayed cutaneous hypersensitivity, in particular to tuberculin, as well as the presence of a high IgG titer against cytomegalovirus (CMV), were correlated to disease progression.

Elevated serum beta-2-microglobulin--a prognostic marker for development of AIDS among patients with persistent generalized lymphadenopathy.

SummaryFor evaluation of its prognostic value, the level of serum β-2-microglobulin was determined in early serum samples from 88 patients with persistent generalized lymphadenopathy in a prospective longitudinal study. Patients with serum β-2-microglobulin >2.6 mg/l were found to have a significantly higher risk of developing AIDS earlier when compared to patients with a lower level (p<0.001).ZusammenfassungIn einer prospektiven longitudinalen Studie wurden in frühen Serumproben von 88 Patienten mit persistierender generalisierter Lymphadenopathie Messungen des β-2-Mikroglobulin-Spiegels vorgenommen, um dessen Wert als prognostischer Faktor zu bestimmen. Das Risiko für den Übergang in AIDS erwies sich bei Patienten mit β-2-Mikroglobulin-Spiegeln von >2,6 mg/l als signifikant höher als bei Patienten mit niedrigeren Spiegeln (p<0,001).

Predictive markers of AIDS: a follow-up of lymphocyte subsets and HIV serology in a cohort of patients with lymphadenopathy

From 1982 to 1985, 89 HIV-1 seropositive men with persistent generalized lymphadenopathy (PGL) were enrolled into a prospective longitudinal study. In February 1988, after a mean observation time of 45 months, 23 patients had progressed to AIDS with opportunistic infection (AIDS/OI), 4 had developed Kaposis sarcoma, 47 had developed HIV-related symptoms, 14 still had PGL as only symptom, and 1 was lost to follow-up. Patients with CD4 lymphocytes less than or equal to 0.40 x 10(9)/l as well as patients with HIV antigenaemia and those lacking antibodies to p24 all had a significantly higher risk of developing AIDS/OI within 30 months of observation than other patients. HIV antigen was present in 70% and antibodies to p24 were lacking in 61% of the patients at the time of AIDS/OI diagnosis. All but one (96%) of the AIDS/OI patients had CD4 numbers less than or equal to 0.20 x 10(9)/l at the same time. The estimated median time to AIDS/OI in patients with HIV antigenaemia was 21 months and in patients lacking p24 antibodies 27 months. In patients with CD4 numbers less than or equal to 0.20 and 0.40 x 10(9) cells/l the estimated median time to AIDS/OI was 14 months and longer than 30 months, respectively.

Relation between skin anergy, lymphadenopathy and T-cell subsets in Swedish homosexual men.

Reversed T-helper/T-suppressor ratios were found in 20/43 symptomatic homosexual men. A significant lower number of T-helper cells was found in patients with skin anergy. No differences were noticed in total lymphocytes or in any of the other T-cell subsets, when subjects with and without skin anergy or lymphadenopathy were examined.