Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS

Abstract

Animal and human lentiviruses elude host defences by establishing covert infections and eventually cause disease through cumulative losses of cells that die with activation of viral gene expression. We used polymerase chain reaction in situ double-label methods to determine how many CD4+ lymphocytes are latently infected by human immunodeficiency virus (HIV) in patient lymph nodes and whether the pool of infected cells is large enough to account for immune depletion through continual activation of viral gene expression and attrition of cells responding to antigens. We discovered an extraordinarily large number of latently infected CD4+ lymphocytes and macrophages throughout the lymphoid system from early to late stages of infection, and confirmed the extracellular association of HIV with follicular dendritic cells. Follicular dendritic cells may transmit infection to cells as they migrate through lymphoid follicles. Latently infected lymphocytes and macrophages constitute an intracellular reservoir large enough ultimately to contribute to much of the immune depletion in AIDS, and represent a difficult problem that must be resolved in developing effective treatments and protective vaccine.

Involvement of cytolytic and non-cytolytic T cells in the control of feline immunodeficiency virus infection

“…To address this question, the distribution of FIV proviral DNA was quanti®ed in the lymphoid tissues throughout the study and compared with the virusspeci®c cellular immune responses. By analogy with studies on virus kinetics following HIV-1 infection, the relatively high proviral burden maintained in the blood until the termination of the study was rather surprising, as it is recognised that HIV-1 proviral burdens are low in the blood of human patients during the asymptomatic phase of the disease (Ogg et al, 1998) with sequestration of HIV-1 to lymph nodes (Embretson et al, 1993;Pantaleo et al, 1993). Our ®ndings may re¯ect the intraperitoneal route of challenge used in this study, coupled with the use of a highly pathogenic isolate of FIV.…”

Effect of Antiretroviral Therapy on Apoptosis Markers and Morphology in Peripheral Lymph Nodes of HIV-Infected Individuals

“…However, the regulatory processes that are important for immune recovery take place in the lymphoid tissue which acts as a viral reservoir and major site of HIV replication. HIV preferentially replicates in CD4+ T lymphocytes, and virus production is 5 to 10 times higher in the lymphoid tissue than that in the peripheral blood lymphocytes [4][5][6]. Therefore, we compared lymph nodes that were excised from 31 previously untreated HIV-infected patients before therapy and after 16-20 months of antiretroviral therapy with respect to lymph node architecture, the distribution of cellular and viral markers, and the expression of apoptotic key molecules.…”

Cell reservoirs in lymph nodes infected with HIV-1 subtype E differ from subtype B: identification by combined in situ polymerase chain reaction and immunohistochemistry

“…The host is able to curtail viral replication but cannot eliminate the virus, leading to a chronic infection with a long period of clinical latency in which lymph nodes act as reservoirs for the virus. [18][19][20] The virus appears to escape elimination by clonal deletion of specific cytotoxic lymphocytes and sequestration of these cells away from the sites of viral replication. Detection of virus and identification of viral reservoirs is important to a more complete understanding of the pathogenesis of this disease.…”

“…Identification of the actual cells that are infected has been carried out using in situ RT-PCR to detect single copies of HIV-1 in infected cells. 18,[21][22][23][24][25][26][27][28] Previous in situ RT-PCR studies (presumably on subtype B) have localized the virus to lymph node germinal centres [29][30][31] either as free virus 30 or in association with CD21 þ follicular dendritic cells or macrophages, 18,25,26,[28][29][30][31][32][33] but not interdigitating dendritic cells. 32 It has been proposed that CD4 þ lymphocytes become infected as they contact follicular dendritic cells in transit through lymph node germinal centers.…”

“…32 It has been proposed that CD4 þ lymphocytes become infected as they contact follicular dendritic cells in transit through lymph node germinal centers. 18,33 The result is a steady rate of T-cell infection, and eventual depletion of T cells. Circulating CD4 þ T cells contain the virus 22,33 and can disseminate the infection systemically.…”