CD4 T CELL ASSESSMENTS IN EVALUATION OF HIV THERAPEUTICS - Flow Cytometry in Drug Discovery and Development - page 167

This chapter will illustrate the prognostic value of CD4 as an immunological
marker in the first AZT trials, which led to its current use as an immunological end
point in clinical trials of ARV drugs and in patient management to detect its adherence
and resistance to ARV therapy. It will also examine the role of CD4 T cell counts in
guidelines on ARV therapy and prophylaxis against opportunistic infections. Finally,
the chapter will discuss the evolution of CD4 enumeration strategies since the
discovery of the HIV virus. This discussion will include the future of CD4 assessment
methodology and technology such as developing testing alternatives aimed at getting
low-cost monitoring to patients in resource-limited settings.

8.2 HISTORICAL BACKGROUND OF THE HUMAN
IMMUNODEFICIENCY VIRUS

Between 1979 and 1981, health clinics throughout the United States saw an
unexpected increase in the treatment of men who have sex with men who presented
with Pneumocystis carinii pneumonia and a relatively rare skin cancer, Kaposi's
sarcoma [3-6]. Most of these same patients also presented with a series of other
opportunistic infections, including oral mucosal candidiasis and cytomegalovirus
(CMV) infection. These opportunistic infections had rarely been seen before, but
independent research groups in NewYork and California began to report high rates of
these infections among men who have sex with men who had previously been healthy.
Subsequent immunological testing revealed that the patients had a reduced percen-
tage and absolute number of T cells and a significant decrease in the helper T cell
(CD4 cell) population [3-10]. Scientists hypothesized that this severe immunode-
ficiency and the resulting opportunistic infections could be the result of a newly
acquired syndrome caused by an unknown infectious agent. In May 1983, the human
immunodeficiency virus was finally isolated from an AIDS patient and was char-
acterized as a retrovirus belonging to the human T cell leukemia viruses (HTLV)
group [8, 9].
HIVwas found to selectively target and destroy CD4 T cells by binding to the CD4
antigen using the chemokine receptor 5 (CCR5) or CXC chemokine receptor 4
(CXCR4) to replicate in the body [10]. HIV causes a virtual complete depletion of
CD4 T cells as levels can drop to an average of 60% of their original number within
12-18 months after seroconversion [11]. This depletion has a devastating effect on
host immunity because it ultimately reduces the production of B cells, monocytes, and
natural killer cells [10]. The compromised immune system is not capable of producing
a robust enough response to pathogens, which ultimately results in morbidity and
mortality in the patient without therapeutic intervention. The destruction of the CD4 T
cells correlates with the onset of AIDS [12]. AIDS is clinically defined as having
HIV infection and a CD4 count less than 200 cells/

m

L; however, studies suggest that
HIV-infected patients can progress to AIDS with CD4 counts ranging from 150 to
300 cells/mm 3 during 12-36 months [13, 14]. When CD4 counts are less than
200 cells/ m L, patients with HIV infection are more susceptible to developing the