Parameter Estimation

Lymphocytes are white blood cells responsible for specific immune response. On the basis of cell membrane components and functions, lymphocytes can be broadly sub-divided into three (3) populations: B cells, T cells and Null cells. Mature B cells can be distinguished from other lymphocytes by the presence of membrane bound immunoglobulin (antibody) molecules, which serve as receptors for antigens. T lymphocytes also have membrane genes within the major histocompatibility complex (MHC). Different lineages or maturational stages of lymphocytes can be distinguished by their expression of membrane molecules recognized by particular monoclonal antibodies.

All monoclonal antibodies that react with a particular membrane molecule constitute a cluster of differentiation (CD). T cells that express CD4 recognize antigens associated with class II MHC molecules and as such function as T helper (TH) cells whereas T cells expressing CD8 recognize antigens associated with class I (MHC) and such cells function generally as T cytotoxic (TC) cells. The generation of both humoral and cell mediated immune responses depends on the activation of TH cells and therefore TH cells have been described to have a central role in acquired immunity.⁷³

Null cells are a small group of peripheral blood lymphocytes, which fail to express membrane molecules that distinguish B and T lymphocytes.

Infection by HIV occurs via binding of viral gp 120 envelope protein to specific

cellular receptor which has been shown to be part of the CD4 molecule present on the surfaces of helper/inducer T lymphocytes, monocytes, macrophages, microglial cells in the brain, chromaffin cells in the intestine, Langerhans’ cells in the skin, rectal mucosa and haematopoetic stem cells.⁷² The virus gains entry into the host cell cytoplasm, it uncoats and the reverse transcriptase enzyme generates a proviral DNA intermediate.

This intermediate then enters the cell nucleus and through the viral integrase enzyme, the viral DNA integrates into the host cell chromosomes. The virus at this point may either remain latent there or be transcribed again into viral messenger RNA (mRNA) and genomic RNA. Thereafter the viral mRNA is translated into the viral proteins, which along with genomic RNA are assembled into new viral particles at the cell surface and leave the virus by budding. The basis of viral latency is poorly understood, it is thought to be determined by the overall state of cellular activation⁷⁴. The activated T-cells showed up regulation of CD4 receptors and were thus more susceptible to infection with HIV and viral replication than resting T-cells.⁷⁴

Reports suggest that the half life of infected CD4 lymphocytes is extremely short (approximately 2 days), and large numbers of viruses are produced in infected persons, even in early stages of infection.⁷⁵ Several workers^68,72 have observed that the hallmark of HIV infection is generalized immunosupression due to progressive depletion as well as functional abnormalities of the CD4 T-cell subtype of lymphocytes.

A number of possible pathogenetic mechanisms of CD4 T-cell destruction have been suggested. These include single cell killing through direct HIV-mediated cytopathic effects resulting from the accumulation of unintegrated viral DNA or from the inhibition of cellular protein synthesis, both of which lead to impaired cell viability and function.

Indirect cell killing occurs via the formation of syncytia of giant multinucleate cells from the direct fusion of cell membrane of an infected cell with the cell membranes of uninfected CD4 cells and eventually leading to cell lysis.

Other postulated mechanisms of indirect cell killing include autoimmune mechanisms as well as virus specific immune responses mediated through HIV-specific cytotoxic T lymphocyte, and antibody dependent T cell cytotoxicity, leading to killing of HIV-infected cells that express viral envelope proteins on their surfaces. Also proposed as a mechanism is inappropriate signaling to cells, leading to programmed cell death (apoptosis) and a state of anergy. This makes the CD4 cells to become refractory to stimulation caused by binding of the gp 120 antigen/antibody complexes to CD4 molecules. The final proposed mechanism is through the activities of retrovirally encoded superantigens, which bind to the variable B region of the T-cell antigen receptor and induce massive stimulation and expansion of T cells leading to anergy or deletion.

All the major immunological pathways have been shown to be affected either directly or indirectly by HIV infection. The most consistent feature is the gradual diminution of CD4 T-lymphocytes from the peripheral blood, both qualitatively and quantitatively leading to gradual but eventual paralysis of the cellular immune system.⁶⁸ In addition, it has been documented that HIV infection causes reversal of the T-helper to T-suppressor cell ratio, cutaneous anergy, decreased lymphocyte proliferative response to mitogens and antigens, impaired natural killer cell activity and impaired cytotoxic T-cell killing of virally infected and cancerous cells.⁷⁵ Furthermore, in HIV infection, there are functional abnormalities in the phagocytic and antigen presenting functions of monocytes and macrophages, as well as in the maturation and differentiation of B-lymphocytes.

Polyclonal B-cell activation and non-specific polyclonal hypergammaglobulinaemia involving mainly IgG and IgA have also been shown to be a major feature of B-cell dysfunction in HIV infection.^68,76

2.5 CELLULAR IMMUNITY AND AETIOLOGY OF