HIV 2

The human immune system and HIV Specific immune responses, antibodies such as IgG, IgA and IgM,
fight viral or intracellular bacterial organisms before they attach to host cells (Yang and Hill, 1996). Killer T cells (cytotoxic T lymphocytes/CD8+), along with the major histocompatibility complex Class I antigen, kill host cells that display foreign characteristics (i.e. antigenic
characteristics) on their surface.Tcells and macrophages augment the ‘killer T cells’ by producing cytokines (secreted by T and B cells and monocytes, which act as messengers in the immune system) such as IL-2, gamma-interferon (IFN-gamma) and IL-12. After the virus enters the cell, specific lymphocyte-mediated cellular immunity induces cytokines that restrain viral replication or evoke cellular cytotoxicity
against virus-infected cells (Proffitt and Yen-Lieberman, 1993; Yang and Hill, 1996). Most microbial infections can be eliminated through this process within 10 days to 2 weeks (Yang and Hill, 1996).

HIV-1 mainly targets CD4+ T lymphocytes (white blood cells that recognize and remember foreign antigens) and CD4+ cells of monocyte/ macrophage lineage which search and destroy foreign agents (Dimmock and Primrose, 1987; Connor and Ho, 1994). T4 cells may be lost through HIV infection by a number of processes. For instance, defects in T4 cells caused by HIV infection may produce activation-induced cell death or normal cell death (apoptosis; Pantaleo
et al., 1993). HIV may also trick the immune system into attacking itself (Kion and Hoffmann, 1991). For instance, syncytia formation involves the massing of healthy T cells around a single-HIV infected T4 cell that results in loss of immune function (Gelderbloom et al., 1985; Hoxie et al., 1986; Sodroski et al., 1986; Stine, 2000). Also, death of
cells could be due to direct membrane disruption involving calcium channels (Gupta and Vayuvegula, 1987) and/or phospholipid synthesis (Lynn et al., 1988). A build-up of un-integrated proviral copies of HIV DNA may cause cytopathology since it is associated with
cell death in other retroviral systems (Levy, 1988). However, it is believed that depletion of T4 cells is insufficient to cause AIDS because not enough T4 cells are destroyed. Equally important may be T4 cell infection of monocytes and macrophages that engulf and destroy antigens (Bakker et al., 1992).
HIV usually puts a portion of its virus on the surface of the cell that it infects. Killer cells, cytotoxic T lymphocytes (CTL), search out and destroy infected cells. But HIV escapes detection by CTLs because Nef, an HIV gene, makes infected cells difficult to identify (Cohen,
1997). There is also a temporal change in viral tropism (affinity) during the course of HIV infection. Early in infection, HIV strains with an affinity for macrophages (macrophage tropic (M-tropic) viruses) have the ability to infect macrophages and are non-syncytium inducing
(NSI) due to their inability to form syncytia on T-cell lines
(Fenyo et al., 1988; Schuitemaker et al., 1992; Connor et al., 1993; Zhu et al., 1993). Usually about four to five years after infection, virus strains evolve in some individuals (about 50%) that can infect T-cell lines in addition to primary T cells (Tersmette et al., 1989; Shioda et al., 1991; Milich et al., 1993). In this change in tropism the viral strains sometimes lose their ability to infect macrophages but more often they retain this property and are referred to as ‘dual tropic’ (Collman et al., 1992). HIV strains that can infect T-cell

lines are referred to as T-tropic, syncytium-inducing (SI). Strains that can grow on transformed cell lines by continual passage are called T-cell line adapted (TCLA: Doms and Moore, 1997). Others display tropism differently with macrophages being infected efficiently and T cell lines less efficiently (Moore and Ho, 1995; Sullivan et al., 1995; Fenyo et al., 1997). This switch may be related to the colonization
of different types of cells by HIV variant strains or a product of natural/host selection in which certain HIV strains (and
their phenotypes) are selected for and escape the immune response (Weiss, 1996).
CD4 receptors alone are sufficient for binding HIV to T4 lymphocyte membranes but co-receptors are required to mediate entry of HIV-1 into cells (see Figure 2.1). The best known HIV co-receptors are CXCR4 and CCR5 members of the CXC and CC chemokine (also called cytokine) receptor subfamilies, respectively (Dragic et al., 1996; Doms and Moore, 1997; Fenyo et al., 1997). CCR5 is the primary
co-receptor for HIV-1 isolates with the NSI phenotype (Deng
et al., 1996; Dragic et al., 1996; Fenyo et al., 1997) while SI phenotypes are associated with the use of CXCR4 alone or in conjunction with
CCR5 (Simmons et al., 1996; Zhang et al., 1996; Fenyo et al., 1997).
Studies show that in the presence of CD4 and the appropriate coreceptor both SI and NSI strains can induce syncytium formation.
Therefore the terms SI and NSI are not absolute but are related to co-receptor expression levels on target cells (Deng et al., 1996; Fenyo et al., 1997).
CD8 T lymphocytes partly control HIV infection by the release of HIV-suppressive factors, beta chemokines that are active on monocytes and lymphocytes. Beta-chemokines MIP-1α, MIP-1β and RANTES are most active against HIV-1 in combination and
inhibit infection of CD4+ T cells by primary, NSI HIV-strains at the virus entry stage. But TCLA/SI HIV-1 strains are insensitive to beta-chemokines. Therefore some CD4+T-helper cells from HIV-1 exposed uninfected individuals resist infection with NSI strains (by secreting high levels of beta-chemokines) but are infected by TCLA/SI strains. It is unknown if high levels of these chemokines can delay HIV disease progression (Cocchi et al., 1995).