Tracking human immunodeficiency virus-type 1 (HIV-1) infection at the cellular level in tissue reservoirs provides opportunities to better understand the pathogenesis of infection and to rationally design and monitor therapy. A quantitative technique was developed to determine viral burden in two important cellular compartments in lymphoid tissues. Image analysis and in situ hybridization were combined to show that in the presymptomatic stages of infection there is a large, relatively stable pool of virions on the surfaces of follicular dendritic cells and a smaller pool of productively infected cells. Despite evidence of constraints on HIV-1 replication in the infected cell population in lymphoid tissues, estimates of the numbers of these cells and the virus they could produce are consistent with the quantities of virus that have been detected in the bloodstream. The cellular sources of virus production and storage in lymphoid tissues can now be studied with this approach over the course of infection and treatment.
Potent combinations of antiretroviral drugs diminish the turnover of CD4؉ T lymphocytes productively infected with HIV-1 and reduce the large pool of virions deposited in lymphoid tissue (LT). To determine to what extent suppression of viral replication and reduction in viral antigens in LT might lead correspondingly to repopulation of the immune system, we characterized CD4؉ T lymphocyte populations in LT in which we previously had quantitated viral load and turnover of infected cells before and after treatment. We directly measured by quantitative image analysis changes in total CD4؉ T cell counts, the CD45RA؉ subset, and fractions of proliferating or apoptotic CD4؉ T cells. Compared with normal controls, we documented decreased numbers of CD4؉ T cells and increased proliferation and apoptosis. After treatment, proliferation returned to normal levels, and total CD4؉ T and CD45RA؉ cells increased. We discuss the effects of HIV-1 on this subset based on the concept that renewal mechanisms in the adult are operating at full capacity before infection and cannot meet the additional demand imposed by the loss of productively infected cells. The slow increases in the CD45RA؉ CD4؉ T cells are consistent with the optimistic conclusions that (i) renewal mechanisms have not been damaged irreparably even at relatively advanced stages of infection and (ii) CD4؉ T cell populations can be partially restored by control of active replication without eradication of HIV-1.
Potent antiretroviral therapy can reduce plasma HIV RNA levels below the threshold of detection for periods of a year or more. The magnitude of HIV RNA reduction in the lymphoid tissue in patients with suppression of HIV RNA levels in plasma beyond 6 months has not been determined. We evaluated levels of HIV RNA and DNA and characterized resistance mutations in blood and inguinal lymph node biopsies obtained from 10 HIV-infected subjects who received 36-52 weeks of indinavir (IDV)͞zidovudine (ZDV)͞lamivudine (3TC), IDV, or ZDV͞3TC. After 1 year of therapy, viral RNA levels in LN of individuals remained detectable but were log 10 ؍ 4 lower than in subjects on the triple drug regimen with interruption of therapy or in those treated with ZDV͞3TC alone, who had viral loads in their lymph nodes indistinguishable from those expected for untreated patients. In all cases viral DNA remained detectable in lymph nodes and peripheral blood mononuclear cells (PBMC). When plasma virus suppression was incomplete, lymph node and PBMC cultures were positive and drug resistance developed. These studies indicate that pronounced and sustained suppression of plasma viremia by a potent antiretroviral combination is associated with low HIV RNA levels in the lymph nodes 1 year after treatment. Conversely, the persistence of even modest levels of plasma virus after 1 year of treatment reflects ongoing viral replication, the emergence of drug resistance, and the maintenance of high burdens of virus in the lymph nodes.Reduction in plasma HIV RNA levels is an indicator of antiretroviral activity in the testing of new compounds and a measure of therapeutic efficacy in the clinical management of HIV-infected patients (1). Plasma virus levels become and remain undetectable by HIV RNA quantitative assays in individuals treated with potent combination antiretroviral regimens (2, ‡ ‡ ). The corresponding response to antiretroviral therapy in the lymphoid tissues, where the vast majority of virus burden resides (3, 4), has not been characterized beyond 6 months of treatment. Reports correlating reductions in levels of HIV RNA in lymph nodes (LN) and plasma in subjects treated with nucleoside analogs have been contradictory (5-9).We examined peripheral blood and biopsied LN from 10 subjects receiving potent antiretroviral therapy for up to 1 year for HIV RNA and proviral DNA burden, for infectious virus, and for the development of resistance to antiviral drugs. In eight subjects, in situ hybridization (ISH) in combination with quantitative image analysis (QIA) (10, 11) was performed on LN specimens to corroborate the quantitative data based on analyses of bulk nucleic acid extracts and to localize residual virus burden to specific compartments within LN. § § Processing of Blood. Blood was centrifuged at 258 ϫ g for 12 min. Plasma was stored at Ϫ70°C. Peripheral blood mononuclear cells (PBMC) were isolated from the buffy coat by Ficoll͞Hypaque density gradient. PBMC were counted and viability was determined by trypan blue exclusion. Cells...
For the kingdom Animalia, 1,552,319 species have been described in 40 phyla in a new evolutionary classification. Among these, the phylum Arthropoda alone represents 1,242,040 species, or about 80% of the total. The most successful group, the Insecta (1,020,007 species), accounts for about 66% of all animals. The most successful insect order, Coleoptera (387,100 species), represents about 38% of all species in 39 insect orders. Another major group in Arthropoda is the class Arachnida (112,201 species), which is dominated by the mites and ticks (Acari 54,617 species) and spiders (43,579 species). Other highly diverse arthropod groups include Crustacea (66,914 species), Trilobitomorpha (19,606 species) and Myriapoda (11,885 species). The phylum Mollusca (117,358 species) is more diverse than other successful invertebrate phyla Platyhelminthes (29,285 species), Nematoda (24,783 species), Echinodermata (20,509 species), Annelida (17,210 species) and Bryozoa (10,941 species). The phylum Craniata, including the vertebrates, represents 64,832 species (for Recent taxa, except for amphibians): among these 7,694 described species of amphibians, 31,958 species of “fish” and 5,750 species of mammals.
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