Loss of Inducible Virus in CD45RA Naive Cells After Human Immunodeficiency Virus-1 Entry Accounts for Preferential Viral Replication in CD45RO Memory Cells

Abstract

Controversy exists concerning the preferential infection and replication of human immunodeficiency virus-1 (HIV-1) within naive (CD45RA+) and memory (CD45RO+) subsets of CD4+ lymphocytes. To explore the susceptibility of these subsets to HIV-1 infection, we purified CD45RA+/CD4+ (RA) and CD45RO+/CD4+ (RO) cells from normal donors and subjected them to a novel monokine activation culture scheme. Following HIV-1 infection and interleukin-2 (IL-2) induction, viral production measured on day 13 was 19-fold greater in RO cultures compared with RA cultures. IL-2–stimulated proliferation in uninfected control cultures was equivalent. To explore the mechanisms by which RA cells were reduced in viral production capacity, RA and RO cells were exposed to HIV-1 followed by treatment with trypsin, and then phytohemagglutinin antigen (PHA)-stimulated at days 4, 7, and 10 postinfection. HIV-1 production in day 4 postinfection RA and RO cultures was analogous, indicating that viral fusion and entry had occurred in both cell types. However, whereas similarly treated day 7 and 10 postinfection RO cultures produced virus, HIV-1 was markedly reduced or lost in the corresponding RA cultures. These results suggest that a temporally labile postfusion HIV-1 complex exists in unstimulated RA cells that requires cellular activation signals beyond that provided by IL-2 alone for productive infection.

T‐Cell inactivation and immunosuppressive activity induced by HIV gp41 via novel interacting motif

“…Thus, the localization of the immunosuppressive motif in FP [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] suggests that the APC/T cell physical interaction is exploited by the virus to simultaneously invade the T cell and interfere with T cell activation. Taken together with the fact that HIV pref-erentially infects HIV specific T cells (29 -32), our observations might explain the unsolved puzzle of decreased HIV-specific T cell immunity amid general T cell hyperactivation observed in HIV-infected patients in the early stages of the infection (33,34). Other immunosuppressive activities described for HIV might collaborate in the takeover of the immune response that finally leads to the collapse of the host's immune system (25,35).…”

Human intestinal lamina propria lymphocytes are naturally permissive to HIV-1 infection

“…Notably, CXCR4 is mainly expressed on naive CD4 + T lymphocytes (CD45RA), while CCR5 is predominantly expressed on memory CD4 + T lymphocytes (CD45RO) [8]. Some studies have suggested that the differentiation of human CD4 + T cells toward a memory phenotype is associated with an increased susceptibility to HIV-1 infection [11][12][13][14]. Notably, most of human intestinal lamina propria lymphocytes (LPL) are memory T cells and are in a peculiar "activation state" [15][16][17].…”

Effects of human immunodeficiency virus type 1 on CD4 lymphocyte subset activation

“…Controversy goes on regarding the susceptibility of RA and RO cells to HIV and whether these subsets are lost or functionally altered in the course of HIV-1 infection. Several cross-sectional and longitudinal studies investigating CD4 subsets in HIV + individuals detected a decline in CD4RA lymphocytes that correlates with the progression of disease [21][22][23][24][25]. These findings reveal that the loss of naive cells begins relatively early after infection, when the infected individuals are otherwise asymptomatic and still have substantial levels of CD4 T cells, and involves both CD4 and CD8 subsets.…”

“…In this context, recent findings also show a preferential decline in naive T cell numbers that correlates with progression of HIV disease and with disruption of the T cell repertoire [24]. In vitro studies indicate that CD4CD45RA and RO populations display a comparable susceptibility to HIV-1 entry and to virus replication [25,26]. However, only infected memory cells undergo apoptosis upon mitogen stimulation, suggesting a differential sensitivity of the RA and RO subset to HIV-1 infection [26].…”