Page 579 - Clinical Immunology_ Principles and Practice ( PDFDrive )

556 ParT fOur Immunological Deficiencies

even among participants who had baseline CD4 counts >500
3
cells/mm . Earlier ART initiation appears to increase the prob-
ability of restoring normal CD4 counts, a normal CD4/CD8
ratio, and lower levels of immune activation and inflammation, Trp62
24
as summarized in the US adult treatment guidelines. Individuals
initiating ART during the first 6 months after infection also
appear to achieve lower immune activation levels and better
immune function during ART-mediated viral suppression
compared with those who delay therapy. 25
Recommendations for initiating therapy in children have
always been relatively more aggressive compared with those for Phe43
adolescents and adults because most infected children were
26
infected perinatally and experience rapid disease progression.
The decision to initiate ART should always include consideration Arg59
of a patient’s comorbid conditions, willingness, and readiness fIG 39.8 Epigallocatechin gallate (EGCG) binding to CD4. Recent
to initiate therapy. ART may be deferred because of clinical or studies indicate that polyphenolic EGCG, a component of green
psychosocial factors, with the goal of initiating therapy as soon tea, can bind to the human immunodeficiency virus (HIV) binding
as possible once barriers to successful treatment have been site of CD4 (KD = 10 nM, as measured by nuclear magnetic
reduced. spectroscopy) and potentially interfere in viral infection by
Antiretroviral Agents interaction with three key amino acids in the D1 domain of the
CD4 molecule (tryptophan 62, phenylalanine 43, and arginine
There are more than 20 approved ARV drugs that are classified 59). (From Williamson MP, et al. Epigallocatechin gallate, the
into six classes based on their chemical structure or the viral main polyphenol in green tea, binds to the T-cell receptor, CD4.
lifecycle step that they inhibit (see Fig. 39.7). The classes of ARV J Allergy Clin Immunol 2006; 118: 1369–74.)
agents currently available include NRTIs, NNRTIs, PIs, fusion
inhibitors, integrase inhibitors, and CCR5 antagonists.
Upon start of ART in patients who are compliant and able to
Reverse Transcriptase Inhibitors, Protease Inhibitors, and tolerate the regimen, the initial CD4 T-cell count is the best
Integrase Inhibitors predictor of a successful outcome. Rapid reduction in the viral
Modified versions of cellular nucleosides, NRTIs, once triphos- load, often to an undetectable level, is one of the earliest changes
phorylated in vivo, are incorporated into the proviral DNA by following initiation of ART, reflecting the ability of combination
HIV reverse transcriptase (RT) and induce premature chain ART to rapidly suppress viral replication. Lagging behind the
termination, thereby inhibiting successful conversion of the viral drop in viral load is the rise in CD4 T-cell values. An initial
RNA to DNA. NNRTIs bind to RT and induce a conformational increase in circulating cells occurs in 3–6 months as a result
change such that RT is unable to bind with nucleotides. PIs act of a decrease in immune activation and subsequent migration
+
+
on viral protease, preventing the cleaving of the posttranslational of memory T cells (CD4 , CD45RO ) out of the lymphoid
viral polyproteins necessary for the maturation and infectivity compartment. A more gradual rise in total CD4 T cells occurs
of viral particles. Integrase inhibitors prevent strand transfer of over the course of 3–5 years with the appearance of new naïve
+
+
+
viral DNA and thus block the incorporation of the completed (CD4 , CD45RA , CD62L ) and memory T cells. Interestingly,
HIV DNA copy into the host-cell DNA. a substantial minority of patients never reach a normal level of
CD4 T cells but, instead, reach a plateau at lower levels. Primary
Fusion Inhibitors, CCR5 Blockers, and drug prophylaxis and some secondary drug prophylaxis for
Low-Molecular-Weight Inhibitors opportunistic infections may be discontinued in patients once
3
Fusion inhibitors and CCR5 antagonists inhibit HIV entry into the CD4 T-cell count reaches >200 cells/mm and is maintained
host cells. Fusion inhibitors bind to viral gp41 and block the for more than 3–6 months. Cellular and humoral responses to
conformational changes necessary to induce fusion of the viral most pathogens also recover with rising CD4 T-cell counts. Of
particle with the host cell. CCR5 antagonists bind to the CCR5 interest, a low CD4 T-cell count at the time of initiating therapy
chemokine coreceptor on host cells, inducing a conformational predicts a poor response to bacterial vaccines even after recovery
change that impedes CCR5 interaction with HIV gp120, thereby of CD4 T-cell levels, suggesting a lag in the return of naïve CD4
preventing HIV entry into host cells. T cells.
Low-molecular-weight inhibitors of HIV binding to the
CD4 molecule are a new approach. Epigallocatechin gallate, by
blocking gp120 binding to the CD4 molecule, has been shown CLINICaL PEarLS
to inhibit the infections of CD4 T cells in culture by wild-type Immunoreconstitution Inflammatory
viruses, setting the stage for a phase I/II study in humans Syndrome (IRIS)
(Fig. 39.8). 27
• IRIS is typically found 2–3 weeks after initiating antiretroviral therapy
IMMUNORECONSTITUTION AFTER THERAPY (ART).
• Patients often become profoundly ill and require hospitalization.
Return of T Cells: Memory T Cells, Then Naïve T Cells • Steroids are sometimes useful in the treatment.
• Clinicians may prevent IRIS by initiating ART only after treating
To varying degrees, the immune system is able to recover following opportunistic infections.
28
initiation of therapy, a process called immunoreconstitution.