Pathology - By W. Keith Henry, MD. Explaining, Predicting, and Treating HIV-Associated CD4 Cell Lo

Author

By W. Keith Henry, MD. Explaining, Predicting, and Treating HIV-Associated CD4 Cell Lo

Don Saklad

2006-10-12, 8:30 am

By W. Keith Henry, MD

Send to a friend ¥

Topic Collections ¥
Genetic Counseling/ Testing/ Therapy ¥
Genetic Disorders ¥
Prognosis/ Outcomes ¥

Explaining, Predicting, and Treating HIV-Associated CD4 Cell Loss
After 25 Years Still a Puzzle

W. Keith Henry, MD;
Pablo Tebas, MD; H.
Clifford Lane, MD

JAMA. 2006;296:1523-1525

The clinical syndrome of AIDS is due to infection with the human
immunodeficiency virus (HIV), which causes a progressive
immunodeficiency characterized by the loss of CD4 T lymphocytes
coupled with an immunosuppression related to global activation of
the immune system. Since the seminal article by Mellors et al in
1996,1 it has been known that as a group, individuals with a
higher HIV RNA viral load tend to progress to AIDS and death at a
more rapid rate than those with lower viral loads, and that
different prognostic information can be derived from the CD4 cell
count and the viral load. The conventional wisdom is that the CD4
cell count represents the current state of immune deficiency,
whereas the viral load reflects the rate at which the immune
system will further deteriorate.2

The report by RodrÂ’guez and colleagues3 in this issue of JAMA
challenges the notion that, at the individual level, a limited
number of HIV measurements over a short period of time provide
meaningful prognostic information regarding the rate of CD4 cell
decline and by extension the risk of opportunistic
infections. Clinicians treating patients with HIV encounter some
patients with low plasma viral levels who experience rapid
progression. What mechanism is responsible for their profound and
quick CD4 cell loss? On the other end of the spectrum are those
patients with high-level HIV viremia who respond clinically like
sooty mangabeys infected with simian immunodeficiency virus
(SIV),4 which can tolerate high levels of SIV replication without
disease progression. Are such patients statistical extremes in an
otherwise simple and uncontested paradigm, or are clinicians and
researchers missing something?

RodrÂ’guez et al have taken the perspective of the individual
patient in attempting to quantify how much of the variability of
the individual CD4 cell loss is explained by the baseline plasma
HIV RNA viral load.3 They used 3 clinical cohorts from several
academic medical centers and confirmed their findings using the
Multicenter AIDS Cohort Study (MACS) public data set, the same
cohort that was used originally by Mellors et al.1 Although the
selection of patients who did not receive treatment immediately
and the relatively short follow-up might have introduced some
bias, the validation in a different well-characterized cohort is
reassuring. The provocative main finding from their study was
that the presenting plasma HIV RNA load predicted no more than
10% of the observed CD4 cell loss in patients with chronic
untreated HIV infection.

What factor(s) explain the other 90%? Twenty-five years into the
HIV epidemic, a complete understanding of what drives the decay
of CD4 cellsÑthe essential event of HIV diseaseÑis still
lacking. Direct and indirect effects of HIV infection, not fully
measured by plasma HIV RNA levels, reverberate through a host's
unique genetic and immunologic environment. HIV persists in
tissues throughout the body and likely sets off chain reactions
of acute and chronic immune disturbances.5 Some of the mechanisms
involved in this process most likely have been identified, but it
is uncertain whether these factors are independent of one
another, driven directly by the virus (or indirectly by the state
of chronic immune activation associated with HIV infection), or a
combination of both. In many cases it is difficult to elucidate
what is cause and what is effect in these observations.

The importance of the host's genetic background in HIV
pathogenesis has been increasingly recognized and
appreciated. For instance, it has been known that some HLA
patterns are associated with slower disease progression6 and that
individuals heterozygous for the {Delta}32 mutation in the CC
chemokine receptor 5 (CCR5) tend to progress more slowly.7
Moreover, proteins like TRIM5 {alpha} make some primate species
resistant to HIV disease,8 and polymorphisms in APOBEC3G9 may
play a role in disease progression. Other recently reported
likely important genetic factors potentially influencing HIV
progression include CCL3L1 gene duplications10 and polymorphisms
in genes participating in postentry steps of the HIV-1 life cycle
(PML, TSG101, and PPIA).11

The acute phase of HIV infection may cause profound damage to the
immune system that may not be clearly linked to ongoing levels of
HIV viremia observed during the chronic phase. Events that occur
during acute HIV infection in the resting memory CD4 cells in
intestinal mucosa might herald risk for subsequent disease
progression, yet the degree of massive tissue CD4 cell depletion
is not reflected by the level of peripheral CD4 cells.12
Furthermore, residual disturbance of the lymph node
architecture13 and the amount of functional thymic tissue
persisting after aging and HIV-related damage also may influence
CD4 cell restoration.14 Immune activation during the chronic
phase of infection is also important and may be a better
predictor of disease progression than HIV RNA viral load.15 Many
previously disparate processes may ultimately be shown to
significantly interact and affect CD4 function and homeostasis in
the setting of HIV infection. For example, very recent reports
describe the critical role that the up-regulation of the
programmed cell death protein PD-1 in CD4 and CD8 T-cells might
have in the pathogenesis of HIV disease,16 and how blockage of
this protein can reverse immune dysfunction and improve control
of viremia in vitro.17 The puzzle of HIV pathogenesis keeps
getting more pieces added to it.

The findings presented by RodrÂ’guez et al3 provide support to
those who favor nonvirological mechanisms as the predominant
cause of CD4 cell loss; however, these data should be interpreted
with caution, and the issue of a single viral load as a
prognostic marker should be separated from the role of viral
replication in HIV pathogenesis. Measurements of a limited
number of viral load levels may not provide a full picture
regarding the overall impact of viral replication on the patient
over the course of disease. To provide such a picture would
require examination of a time-dose relationship for viral load
and comparison with changes in CD4 T cells over an extended
period of time. In addition, censoring patients who initiated
antiretroviral therapy within 6 months of study may have
eliminated a cohort of patients with the most rapid declines in
CD4 cell counts from the analysis.

The study by RodrÂ’guez et al may have several important clinical
implications. The first and more straightforward is that baseline
measurements of viral load alone should have less of a role in
driving decisions on when to start antiretroviral therapy for an
individual patient; these initial viral load levels cannot
predict how rapidly the disease will progress. Current treatment
guidelines18-19 in the developed world progressively have
recognized the limited role that HIV-RNA level plays in this
decision and have increasingly stressed the importance of the
baseline CD4 cell count. Interestingly, guidelines in the
developing world20 have reached the same conclusions, but have
been based more on economic arguments. The secondary importance
of baseline plasma HIV RNA levels does not diminish its critical
importance in monitoring viral load responses after the
initiation of antiretroviral therapy to document complete viral
suppression and prevent the development of resistance. However,
the seemingly useful practice of combining a CD4 cell count and
plasma HIV RNA levels to assess an individual patient's prognosis
for AIDS progression21 or response to highly active
antiretroviral therapy22 needs reexamination.

The second and potentially more exciting implication of the
findings of RodrÂ’guez et al is that future improvements in the
treatment of HIV infection and AIDS may result from improved
understanding of the 90% of CD4 cell depletion that remains
enigmatic. The current paradigm of HIV treatment is the
continuous use of antiretroviral combinations (targeting the
widespread effects of ongoing HIV replication) for long periods
of time, which now could approximate a normal life span. This
approach has led to the most dramatic change in the prognosis of
any disease in the last 2 decades, from usually lethal to
regularly manageable. However, the sustainability of the current
paradigm for the more than 40 million HIV-infected individuals
and the more than 4 million new HIV infections per year is at
best questionable.23

Unfortunately, treatment strategies that do not directly target
HIV have not proven successful. Only 2 immunomodulators have
been approved for the treatment of HIV-related disease: (1)
interleukin 2, a cytokine used in some European countries to
increase the CD4 cell count24; and (2) thalidomide, a tumor
necrosis factor {alpha} antagonist for aphthous ulcers associated
with HIV infection.25 This is a meager list when compared with
the 24 currently approved antiretroviral drugs, all of which
directly inhibit stages of HIV replication.

As in the treatment of cardiovascular disease, developing
therapeutic strategies for HIV that target both the etiology and
the end organ damage may be more effective than either alone.
Therapies focused on some of the nonviral factors (discussed
above) may start to address the bulk of the "iceberg" below the
tip of the measureable plasma HIV level. A better understanding
of the immunologic and genetic factors that drive HIV-associated
CD4 cell loss may translate to novel therapeutic approaches that
could favorably shift the pathogen-host balance. In that
direction, the first drugs that target a cellular factor (the
chemokine receptor CCR5) have reached the clinical arena and are
currently in phase 3 trials.26-27 Discovering and developing
therapies that target key nonviral factors has the potential over
the decades ahead to build on the success of antiretroviral
therapy and expand access to sustainable effective therapy.

AUTHOR INFORMATION

Corresponding Author:
Keith Henry, MD, Hennepin County Medical Center,
701 Park Ave R7, Minneapolis, MN 55415
keithh6680@aol.com
keithh6680 at aol.com

Financial Disclosures:
Dr Henry reports that he conducts research funded by the
National Institutes of Health,
the Centers for Disease Control and Prevention,
Bristol-Myers Squibb,
Serono,
Thera, and
Pfizer;
is on the speakers bureau for
GlaxoSmithKline,
Bristol-Myers Squibb,
Roche, and
Gilead;
has received honoraria from
GlaxoSmithKline,
Bristol-Myers Squibb, and
Gilead; and
has been a consultant for
GlaxoSmithKline,
Bristol-Myers Squibb, and
Gilead.

Dr Tebas reports that he receives grant support from the
National Institutes of Health,
Pfizer,
Roche,
VIRxSYS,
Tibotec,
Primagen,
Gilead,
VGX, and
Wyeth; has received honoraria from
Bristol-Myers Squibb and
GlaxoSmithKline; and has been a consultant for
Bristol-Myers Squibb and
Primagen.

Dr Lane reports that he has received research support from
Novartis and is a
co-inventor in a US governmentÐheld patent of
interleukin 2 for use in HIV infection.

Editorials represent the opinions of the authors and JAMA and
not those of the American Medical Association.

Author Affiliations:
HIV Program, Hennepin County Medical Center and the
University of Minnesota, Minneapolis (Dr Henry);
Division of Infectious Diseases,
University of Pennsylvania, Philadelphia (Dr Tebas); and
Division of Clinical Research and Laboratory of Immunoregulation,
National Institute of Allergy and Infectious Diseases,
Bethesda, Md (Dr Lane).

REFERENCES

1. Mellors JW, Rinaldo CR Jr, Gupta P, White RM, Todd JA,
Kingsley LA.
Prognosis in HIV-1 infection predicted by the quantity of virus
in plasma.
Science. 1996;272:1167-1170.
ABSTRACT

2. Coffin J
HIV and viral dynamics.
Presented at: 11th International Conference on AIDS;
July 7-12, 1996; Vancouver, British Columbia.

3. RodrÂ’guez B, Sethi AK, Cheruvu VK, et al.
Predictive value of plasma HIV RNA level
on rate of CD4 T-cell decline in untreated HIV infection.
JAMA. 2006;296:1498-1506

4. Rey-Cuille MA, Berthier JL, Bomsel-Demontoy MC, et al.
Simian immunodeficiency virus replicates to high levels
in sooty mangabeys without inducing disease.
J Virol. 1998;72:3872-3886

5. Stebbing J, Gazzard B, Doueck DC.
Mechanisms of disease: where does HIV live?
N Engl J Med. 2004;350:1872-1880

6. Migueles SA, Sabbaghian MS, Shupert WL, et al.
HLA B*5701 is highly associated with
restriction of virus replication
in a subgroup of HIV-infected long term nonprogressors.
Proc Natl Acad Sci U S A. 2000;97:2709-2714

7. Dean M, Carrington M, Winkler C, et al.
Genetic restriction of HIV-1 infection and progression to AIDS
by a deletion allele of the CKR5 structural gene:
Hemophilia Growth and Development Study,
Multicenter AIDS Cohort Study,
Multicenter Hemophilia Cohort Study,
San Francisco City Cohort,
ALIVE Study.
Science. 1996;273:1856-1862

8. Stremlau M, Owens CM, Perron MJ, Kiessling M, Autissier P,
Sodroski J.
The cytoplasmic body component TRIM5alpha
restricts HIV-1 infection in Old World monkeys.
Nature. 2004;427:848-853

9. An P, Bleiber G, Duggal P, et al.
APOBEC3G genetic variants
and their influence on the progression to AIDS.
J Virol. 2004;78:11070-11076

10. Gonzalez E, Kulkarni H, Bolivar H, et al.
The influence of
CCL3L1 gene-containing segmental duplications
on HIV-1/AIDS susceptibility.
Science. 2005;307:1434-1440

11. Bleiber G, May M, Martinez R, et al.
Use of a combined ex vivo/in vivo population approach for
screening of human genes involved in
the human immunodeficiency virus type 1 life cycle
for variants influencing disease progression.
J Virol. 2005;79:12674-12680

12. Brenchley JM, Schacker TW, Ruff LE, et al.
CD4+ T cell depletion during all stages of HIV disease
occurs predominantly in the gastrointestinal tract.
J Exp Med. 2004;200:749-759

13. Schacker TW, Nguyen PL, Beilman GJ, et al.
Collagen desposition in HIV-1 infected lymphatic tissues and
T cell homeostasis.
J Clin Invest. 2002;110:1133-1139

14. Delgado J, Leal M, Ruiz-Mateos E, et al.
Evidence of thymic function in heavily antiretroviral treated
human immunodeficiency virus type 1-infected adults
with long-term virologic treatment failure.
J Infect Dis. 2002;186:410-414

15. Giorgi JV, Hultin LE, McKeating JA, et al.
Shorter survival in advanced human immunodeficiency virus
type 1 infection is more closely associated with
T lymphocyte activation than with plasma virus burden or
virus chemokine coreceptor usage.
J Infect Dis. 1999;179:859-870

16. Trautmann L, Janbazian L, Chomont N, et al.
Upregulation of PD-1 expression on HIV-specific CD8 + T cells
leads to reversible immune dysfunction
[published online ahead of print August 20, 2006].
Nat Med. doi:10.1038/nm1482

17. Day CL, Kaufman DE, Kiepiela P, et al.
PD-1 expression on HIV-specific T cells is associated with
T-cell exhaustion and disease progression
[published online ahead of print August 20, 2006]
Nature. doi:10:1038/nature05115

18. DHHS Panel on Antiretroviral Guidelines
for Adults and Adolescents.
Guidelines for the use of antiretroviral agents in HIV-1
infected adults and adolescents. May 4, 2006
http://aidsinfo.nih.gov/ContentFile...dolescentGL.pdf
Accessed August 29, 2006

19. Hammer SM, Saag MS, Schecter M, et al.
Treatment for adult HIV infection: 2006 recommendations of the
International AIDS Society-USA Panel.
JAMA. 2006;296:827-843.

20. World Health Organization-HIV/AIDS Programme.
Antiretroviral therapy for HIV infection
in adults and adolescents in resource limited settings:
towards universal access: recommendations for
a public health approach: 2006 revision
http://www.who.int/hiv/pub/guidelin...0Guidelines.pdf
Accessed August 29, 2006

21. Mellors JW, Munoz A, Giogi JV, et al.
Plasma viral load and CD4+ lymphocytes as prognostic markers
in HIV infection.
Ann Intern Med. 1997;126:946-954.

22. Egger M, May M, Chene G, et al.
Prognosis of HIV-1 infected patients starting
highly active antiretroviral therapy:
a collaborative analysis of prospective studies.
Lancet. 2002;360:119-129.

23. UNAIDS.
2006 Report on the global AIDS epidemic.
http://www.unaids.org/en/HIV_data/2...ort/default.asp
Accessed August 30, 2006.

24. Kovacs JA, Vogel S, Albert JM, et al.
Controlled trial of interleukin-2 infusions in patients
infected with the human immunodeficiency virus.
N Engl J Med. 1996;335:1350-1356.

25. Jacobson JM, Greenspan JS, Spritzler J, et al,
National Institute of Allergy and Infectious Diseases
AIDS Clinical Trials Group.
Thalidomide for the treatment of oral aphthous ulcers in
patients with human immunodeficiency virus infection.
N Engl J Med. 1997;336:1487-1493.

26. Deeks SG.
Challenges of developing R5 inhibitors in
antiretroviral naÂ•ve HIV-infected patients.
Lancet. 2006;367:711-713.

27. Lederman MM, Penn-Nicholson A, Cho M, Mosier D.
Biology of CCR5 and its role in HIV infection and treatment.
JAMA. 2006;296:815-826.

RELATED ARTICLES

This Week in JAMA
JAMA. 2006;296:1437.

Predictive Value of Plasma HIV RNA Level
on Rate of CD4 T-Cell Decline in Untreated HIV Infection
Benigno RodrÂ’guez, Ajay K. Sethi, Vinay K. Cheruvu,
Wilma Mackay, Ronald J. Bosch, Mari Kitahata,
Stephen L. Boswell, W. Christopher Mathews, David R. Bangsberg,
Jeffrey Martin, Christopher C. Whalen, Scott Sieg,
Suhrida Yadavalli, Steven G. Deeks, and Michael M. Lederman
JAMA. 2006;296:1498-1506.

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Predicting CD4-Cell Decline in HIV-Infected Patients
Journal Watch Infectious Diseases 2006;2006:3-3.

By W. Keith Henry, MD