Berlin: Long-Term Survival Studies Suggest New Treatment Strategies

Many of those attending the IX International Conference on
AIDS in Berlin went away disappointed at the lack of AIDS
treatment breakthroughs. Disappointing reports such as the
Concorde study of early intervention with AZT, and the
apparent failure of the Hoffmann-la Roche tat inhibitor,
suggested that, at least superficially, science was going
backwards. Yet the distressing state of treatment research
masked considerable advances in understanding disease
mechanisms ("pathogenesis") in AIDS. Much of that progress
came from studying the natural success stories: so-called
long-term survivors who remain comparatively healthy despite
many years of living with HIV.

In a conference last February at the National Institute of
Allergy and Infectious Diseases, researchers categorized
three types of long-term survival. First are people who
maintain stable levels of T-helper cells for seven or more
years following infection with HIV. Within this group is
locked the mystery of successful resistance to HIV.
Elucidating the reasons for this success would probably yield
an effective way to manage HIV infection. It is worth noting
that chimpanzees belong to this group -- they become infected
with HIV but do not exhibit symptoms.

In the second category of survival are people who stay
clinically healthy although the T-helper cell population in
their peripheral blood, at least, has deteriorated
significantly. This group presents a dual mystery: How can
the immune system still function without T-cells to
orchestrate it, and why does the HIV infection itself
stabilize after it first escapes immune system control? A
very few people are even able to recover somewhat, with their
T-cell counts bouncing upwards again.

Finally there is a group whose members are not technically
survivors because they never became infected with HIV at all.
These are people whose personal histories indicate extensive
exposures to the virus, through unsafe sex, contaminated
syringes, or blood transfusions, but who show no sign that
they are carrying HIV at present. The key to effective
vaccines may lie within in this group's natural resistance.

The Berlin Conference included extended discussions of the
basis for long-term survival. One obvious factor in survival
is the virulence of an individual's predominant strain of
HIV. But HIV's ability to evolve into more virulent forms
after infection is of secondary importance if that infection
is under control, since mutations cannot develop if the virus
is not reproducing. Participants at the Conference suggested
that differences in personal immune function, genetics and
psychology all influence how a person successfully counters
HIV.

Immune Response

In a major address to the Conference, Jay Levy described his
experience working with healthy non-progressors.(1) Levy's
main finding concerns cytotoxic lymphocytes, certain blood
cells whose usual job is to search out and kill cells
infected with viruses. Levy has found a certain subpopulation
that instead of killing its HIV-containing targets, secretes
a still unidentified chemical that suppresses new virus
production, leaving the HIV inside the cells locked in a
latent phase. In long-term survivors, these cells' activities
strongly persist well after they have declined in most HIV-
infected individuals. Identification and synthesis of this
chemical, which exists naturally in only tiny amounts, could
lead to a potent therapy for controlling HIV. (Dr. Levy first
reported the existence of this chemical in 1986,(2) but
certain details were reported in Berlin for the first time.)

Posters by Landay and others(3) and Ennen and others(4) on
African green monkeys supported Levy's observations about a
soluble HIV-suppressing factor produced by a particular sort
of cytotoxic lymphocyte. Several talks at a session on
"markers of non-progression" stressed the importance of other
types of cytotoxic lymphocytes for long-term survival.(5,6,7)

The work of Mario Clerici and Gene Shearer helps explain what
happens to cause cytotoxic lymphocytes' decline. There is a
partial tradeoff between the cytotoxic lymphocyte arm of the
immune system, which is stimulated by a particular T-helper
cell subset known as Th-1, and the antibody-producing arm,
stimulated by Th-2 helper T-cells. Other concomitant
infections or just increasing levels of HIV may cause the
immune system to emphasize antibody production at the expense
of the cytotoxic lymphocyte arm. Antibodies are good for
fighting bacteria and free viruses, but for HIV their
effectiveness is questionable. The rapidly mutating HIV
replicating within cells is not much affected by antibodies,
and its mutant progeny can escape antibody control even when
released and floating free in the plasma between cells.

A poster by Zvi Bentwich and others(8) described antibody
activation processes in Africans with HIV. In another
poster,(9) Bentwich and his colleagues described detecting
cellular immune defenses against HIV in antibody-negative
sexual partners and children of Africans with HIV. Several
other presentations at the Conference also supported the
particular importance of the cellular (as opposed to the
antibody) immune response, in blocking initial infection in
people with probable multiple exposures to HIV. Among these
were Shearer, Clerici and others on gay men,(10) Clerici and
others(11) on macaque monkeys and Weiss and others(12) on IV
drug users. In all these cases, people or monkeys
consistently tested negative on the standard HIV antibody
test, and usually also in direct tests for the presence of
virus. Yet an immune response did exist on cytotoxic
lymphocyte level, indicating past exposure to and successful
containment or elimination of HIV.

These observations indicate that a treatment to prevent AIDS
could be fashioned from immune modulators that switched or
held the immune response to the Th-1, cytotoxic lymphocyte
mode. One suggestion has been to create a chemical or
antibody that attacks IL-10, a natural messenger molecule in
the body that promotes antibody production while curtailing
the activity of cytotoxic lymphocytes. Another possibility is
the administration of IL-12. IL-12 enhances the activity of
Th-1 cells and has been found to be low in people with
HIV.(13)

It is difficult to predict the ultimate consequences of
playing with the internal balance of the immune cells'
messenger system, which has a wide spectrum of effects.
Blocking IL-10 is problematic if antibodies are needed to
combat a bacterial co-infection, for example. In addition,
Robert Yarchoan, Samuel Broder and others in a presentation
at the conference proposed using IL-10 as an anti-HIV therapy
because it inhibits the virus' replication in monocytes and
macrophages.(14)

Posters by Bentwich(15) and Howard Urnovitz(16) (and, from a
somewhat different perspective, a major address on cofactors
by Luc Montagnier(17)) indicate that an alternative way to
delay disease progression is to actively avoid contracting
co-infections and aggressively treating those that do occur.
Comments by many long-term survivors about ways they have
improved their general state of health fit into this
perspective. Certainly a study comparing the overall health
status of slow progressors versus others with AIDS, and
analyzing the role played by such differences, would be a
very valuable addition to both community and scientific
knowledge on how to delay the onset of the disease.

Genetic Differences

In San Francisco, the City Clinic Cohort was already
functioning before the AIDS epidemic as a Hepatitis B study.
Since then it has been tracking men with HIV and AIDS. The
study has built up a unique collection of blood samples
documenting the transmission of HIV and the course of disease
since the late seventies. Eight percent of the 593 men from
the group with well-defined dates of HIV infection are
considered "healthy long-term positives" -- they have T-
helper cell counts over 500 despite being HIV-positive for
ten years or more.

In analyzing this group, Susan Buchbinder found specific
genetic differences that distinguished the non-
progressors.(18) These differences involved the "major
histocompatibility complex" (MHC), a group of genes that
determines certain cell surface molecules. The MHC molecules
present foreign proteins extracted from invading microbes (or
from cancerous cells) to T-helper cells and cytotoxic
lymphocytes in order to activate immune defenses.

Immune system stimulation depends on the particular shape of
the MHC-foreign protein complex, which must look like a
foreign, or "non-self," protein to immune cells. Since HIV's
gp120 outer coat protein resembles part of the natural T-
helper cell receptor, establishing a healthy immune response
to HIV may be particularly difficult. People with MHC
molecules structured in certain ways may pick pieces of HIV
protein that are more noticeable to the immune system, or the
molecules may present the protein in a more conspicuous way.
And it is an individual's particular MHC genes that the
determine the shape of these molecules.

One poster by Kaslow and others(19) related rapid disease
progression to certain MHC genes that seemed to result in
high levels of a certain class of antibodies (IgA). MHC
genetic differences may well confer protection by the precise
type of immune response they promote in the presence of HIV.
Thus the observations about MHC variations fit in with the
Th-1/Th-2 (cytotoxic lymphocyte versus antibody) conflict
mentioned above. (Costagliola and others(20) also found a
striking detrimental effect in hemophiliac patients from a
certain MHC gene.)

Support for the idea that particular MHC genes have a major
protective effect came from several other studies presented
in Berlin besides Buchbinder's. Dean Mann, of the National
Cancer Institute, described similar findings in a group of
122 men who have been followed since 1983.(21) One type of
gene seemed to result in slower progression early in the
course of the disease, while later on, certain genes of
another class were associated with greater protection against
AIDS. Still others seemed linked with more rapid progression
later on.

A study of a San Francisco woman(22) found similar MHC
genetic advantages similar to the Mann and Buchbinder
studies. The woman received an HIV-contaminated transfusion
in 1981 but remains healthy and with no culturable HIV in her
blood (although she produces HIV antibodies). An
investigation of consistently HIV-negative female prostitutes
in Nairobi(23) as well as a report from a heterosexual
partners study in California(24) found an association between
MHC genes and protection from HIV transmission in people
frequently exposed to the virus.

People tend to despair when the mention of genetic advantages
comes up because knowledge of such advantages seems to offer
no help to those not so endowed. But use of genetic markers
may help to determine who has need of early treatment and
what sort of treatment to offer. MHC-based treatments are
still in the realm of speculation, but might include
cytotoxic lymphocyte stimulators or specific chemicals that
bind to MHC molecule-HIV fragment complexes to make them
mimic the complexes created by people with the more
protective genes. Insights into the effect of MHC molecule
shape may also contribute to the design of more potent
therapeutic and prophylactic vaccines.

Psychology

Personal lifestyle is one aspect that is open to individual
alteration in an effort to slow progression to AIDS. For
example, Susan Caumartin and colleagues at the University of
Michigan presented a poster(25) that found a close linkage
between social affiliations and survival time at every level
of health. Among the indices of social participation used by
the researchers, the one measuring how actively respondents
tried to help other gay men through the epidemic especially
stood out. Social participation also appeared indicative of a
group of other personality traits (optimism, social
integration, lack of denial, health vigilance) that are
considered to prolong survival.

In another commentary Robert Remien, Ph.D., described a group
of 53 long-term survivors of AIDS (three to nine years since
diagnosis) that he and his colleagues had observed in New
York.(26) Remien found that resilience in the face of
adversity was typical of his group. Even up to the time of
death, Remien's long-term survivors maintained a high level
of enjoyment in life and minimal psychological distress.
Reflecting the importance of social connectiveness, Remien
noted that the greatest difficulty the group's members faced
was watching many of their friends die.

Remien listed the following as distinctive characteristics of
long-term survival: Realistically acknowledging life's
challenges and grieving the losses, reframing one's view of
situations so as to keep up a positive attitude, maintaining
goals and an active life, recognizing the value of social
supports, developing a good doctor-patient relationship, and
seeking an active role in managing one's own medical care.
Remien's remarks were seconded by F. Bofinger in a
poster.(27)

In an unabstracted speech during a "roundtable" session on
long-term survival, Rafael Pagn of Puerto Rico described
additional personality factors that contribute to staying
healthy. He thought the "will to live" is central to survival
and recounted how he helps build self-esteem and the ability
to carry on a satisfying sex life after testing positive. Dr.
Pagn's clinic (the Community Network for Clinical Research
on AIDS) is the only gay-oriented and the only HIV-
specialized health facility on the island.

Note, though, that one poster from the Multicenter AIDS
Cohort Study in the U.S. found that psychological depression
at the beginning of the study did not correlate with faster
progression to AIDS or death.(28) A Dutch study also found no
effect on survival time from coping ability at the beginning
of the study,(29) nor was there any noticeable effect from
unsafe sex or intravenous drug use, two other commonly
supposed disease accelerators. Intravenous drug use also was
rejected as a detrimental factor by an American study(30)
conducted by 17 American community-based research agencies
that are part of the Community Program for Clinical Research
on AIDS (CPCRA).

To explain the relationship between psychological factors and
health, one might have to resort to the field of
psychoneuroimmunology and the poorly defined relationship
between mental processes and the immune system. But a large
part of the explanation might be much more straightforward:
People with more "resilience" -- including greater connection
to the outside social world and a more acute awareness of the
nature of AIDS (as opposed to coping mechanisms based on
denial) -- may simply be more able to seek out and demand
better medical care. Their greater health consciousness may
also cause them to reform their daily habits in positive
ways, such as improving their diet.

To cite a specific example, John Mordaunt, one of the
speakers at the conference's final plenary session, is a
long-term survivor and ex-heroin addict now on methadone
maintenance. Mordaunt points out that obtaining clean
syringes and clean drugs by itself strongly protects addicts'
health. As noted above, absence of concomitant infections
seems definitely connected to the quality of the immune
response against HIV.

The extent to which health-promoting behavior (or "health
vigilance") acts as the bridge between the various elements
associated with prolonged survival could not be settled at
the Ninth International Conference on AIDS. Robert Remien
notes that the biologists and the psychologists studying
survival are still in "different camps." Although the Berlin
conference did nothing to bring the different disciplines
together, it did at last provide an occasion to survey what
various fields can now say about resistance to HIV and AIDS.

Further investigation is needed to confirm and expand
previous observations, and some grand, unifying theory is
required to apply the lessons of survival to the development
of therapies. One meeting in Berlin attempted to initiate a
network of long-term survivors and researchers to coordinate
more study of survival factors. Aldyn McKean of ACT UP/New
York, who gave a keynote address to the Conference on the
importance of studying long-term survival, is coordinating
this embryonic association. Those interested in furthering
research into the sources of long-term survival can reach him
at 212/674-2545.

References

1. Levy, JA. HIV pathogenesis and long-term survival.
International Conference on AIDS, Berlin, June 6P11, 1993
[abstract #PS-05-2].

2. Walker CM, Moody DJ, Stites DP, and Levy JA. CD8+
Lymphocytes Can Control HIV Infection In Vitro By Suppressing
Virus Replication. Science. December 19, 1986; volume 234,
number 4783, pages 1563-1566.

3. Landay AL, Mackewicz C, and Levy, JA. Activated CD28+ CD8+
T cell phenotype correlates with anti-HIV suppressing
activity and asymptomatic clinical status. International
Conference on AIDS, Berlin, June 6P11, 1993 [abstract #PO-
A14-0284].

4. Ennen J, Findeklee K, Werner SG, Norley ME, and Kurth R.
CD8+ T-lymphocytes of African green monkeys efficiently
suppress SIVagm replication. International Conference on
AIDS, Berlin, June 6P11, 1993 [abstract #WS-A09-5].

5. Klein MR, Bende RJ, van Baalen CA, Keet IPM, Eeftinck
Schattenkerk JKM, and Miedema, F. Persistent high gagCTLp
frequency and low viral load in long-term asymptomatic HIV
infection. International Conference on AIDS, Berlin, June 6P
11, 1993 [abstract #WS-B03-3].

6. Rivire Y, McChesney M, Porrot F, Tanneau F, Buseyne F,
Regnult A., and others. Role of HIV specific cytotoxic
effector cells in disease progression. International
Conference on AIDS, Berlin, June 6P11, 1993 [abstract #WS-
B03-4].

7. Reiter WM, Vorce DE, Cimoch PJ, Keller RH, Berger DS, and
Ping AC. Cytotoxic CD8+ lymphocyte response to HIV-1
infection correlated with longitudinal analysis of CD4+
lymphocyte percentage. International Conference on AIDS,
Berlin, June 6P11, 1993 [abstract #WS-B03-5.].

8. Bentwich Z, Burstein R, Weisman Z, Kamminsky M, and
Kalinkovich S. Th2 activation and pathogenesis of African
AIDS. International Conference on AIDS, Berlin, June 6P11,
1993 [abstract #PO-A19-0392].

9. Bentwich Z, Jehuda-Cohen T, Bar-Yehuda S, Miltchan R,
Kamminsky M, and Vansover A. HIV specific immunity in
seronegative individuals. International Conference on AIDS,
Berlin, June 6P11, 1993 [abstract #PO-A22-0490].

10. Shearer GM, Clerici M, Berzofsky JA, Pahwa S, Chess L,
and Lederman S. HIV exposure in long-term non-seroconverting
homosexual men at risk for HIV infection. International
Conference on AIDS, Berlin, June 6P11, 1993 [abstract #WS-
A09-4].

11. Clerici M, Axberg I, Polacino-Firpo P, Kuller L, Morton
W, Benveniste R., and others. SIV-specific cellular immunity
in seronegative macaques exposed to siv/Mne. International
Conference on AIDS, Berlin, June 6P11, 1993 [abstract #WS-
A15-3].

12. Weiss SH, Clerici M, Hewlett I, Mayur RK, Berzofsky JA,
and Shearer GM. Evidence of immunologic and virologic
responses to HIV exposure among a high risk but long-term HIV
antibody seronegative (HIV-) cohort of injection drug users
(IDU). International Conference on AIDS, Berlin, June 6P11,
1993 [abstract #WS-A15-5].

13. Chehimi J, Trinchieri G, Frank I, Aste M, Sennelier J,
and Starr SE. IL-12 deficiency in HIV-infected patients.
International Conference on AIDS, Berlin, June 6P11, 1993
[abstract #WS-A08-4].

14. Saville Mw, Tosato G, Taga k, Foli A, Broder S, and
Yarchoan R. Interleukin-10 (IL-10) is a potent inhibitor of
HIV replication in monocyte/macrophages (M/M). International
Conference on AIDS, Berlin, June 6P11, 1993 [abstract #WS-
A08-1].

15. Bentwich Z, Burstein R, Weisman Z, Kamminsky M, and
Kalinkovich S. Th2 activation and pathogenesis of African
AIDS. International Conference on AIDS, Berlin, June 6P11,
1993 [abstract #PO-A19-0392].

16. Urnovitz HB, Sturge J, Gottfried TD, and Robison DJ.
Western blot confirmation of urine HIV-1 envelope antibodies
from EIA seronegative subjects. International Conference on
AIDS, Berlin, June 6P11, 1993 [abstract #PO-A31-0733]

17. Montagnier L. HIV, cofactors and AIDS. International
Conference on AIDS, Berlin, June 6P11, 1993 [abstract #OP-03-
1].

18. Buchbinder S, Mann D, Louie L, Villinger F, Katz M,
Holmberg S., and others. Healthy long-term positives (HLPs):
genetic cofactors for delayed HIV disease progression.
International Conference on AIDS, Berlin, June 6P11, 1993
[abstract #WS-B03-2)

19. Kaslow R, Rinaldo C, Friedman H, Kuo V, Visscher B, and
Phair J. Association of high serum IgA with HLA-A1, Cw7, B8
in men with rapidly progressing HIV infection. International
Conference on AIDS, Berlin, June 6P11, 1993 [abstract #PO-
A23-0507)

20. Sahmoud T, Laurian Y, Cazengel C, Sultan Y, Gautreau C,
and Costagliola D. HLA-B35 and progression to AIDS in
haemophiliac patients. International Conference on AIDS,
Berlin, June 6P11, 1993 [abstract #PO-C04-2672].

21. Mann D, Carrington M, O'Donnell M, Yeager M, Harding A,
and Goedert J. Selected HLA class I and II alleles are
associated with relative rates of disease progression in HIV-
1 infection. International Conference on AIDS, Berlin, June
6P11, 1993 [abstract #WS-A07-6].

22. Schwartz D, Sharma U, Farzedegan H, and Viscidi R. Immune
response without HIV in the blood of a long term survivor.
International Conference on AIDS, Berlin, June 6P11, 1993
[abstract #WS-A21-6].

23. Plummer Fa, Fowke K, Nagelkerke Njd, Simonsen Jn, Bwayo
J, and Ngugi E. Evidence of resistance to HIV among
continuously exposed prostitutes in Nairobi, Kenya.
International Conference on AIDS, Berlin, June 6P11, 1993
[abstract #WS-A07-3].

24. Louie Lg, Just J, Padian N, and King M-C. HLA genotype
and risk of heterosexual HIV transmission. International
Conference on AIDS, Berlin, June 6P11, 1993 [abstract #PO-
B02-0935].

25. Caumartin Sm, Joseph Jg, and Gillespie B. The
relationship between social participation and aids survival
in the Chicago Macs/ccs cohort. International Conference on
AIDS, Berlin, June 6P11, 1993 [abstract #PO-D20-4008].

26. Remien R, Rabkin J, Katoff L, and Wagner, G. Medical and
psychological characteristics of extended longterm survival
with aids: a follow-up study. International Conference on
AIDS, Berlin, June 6P11, 1993 [abstract #WS-D15-3].

27. Bofinger F, Marguth U, Pankofer R, Seidl O, and Ermann M.
Psychological aspects of longterm-surviving with AIDS.
International Conference on AIDS, Berlin, June 6P11, 1993
[abstract #PO-D20-3961].

28. Lyketsos Cg, Hoover Dr, Guccione M, Senterfit W, Dew M,
and Wesch J. Depression does not predict CD4 decline or
future HIV outcomes in the Multicenter Aids Cohort Study
(MACS). International Conference on AIDS, Berlin, June 6P11,
1993 [abstract #PO-B02-0930)

29. Keet Ipm, Krol A, Klein M, Veugelers P, Goudsmit J,
Miedema F, and Coutinho RA. Characteristics of long term
survival early and late in HIV infection. International
Conference on AIDS, Berlin, June 6P11, 1993 [abstract #WS-
C03-3].

30. Brown LS, Neaton J, Wentworth O, and Sherer R. A
national, multi-site HIV disease progression and survival
study in injection drug users (idus) and non-IDUs.
International Conference on AIDS, Berlin, June 6P11, 1993
[abstract #WS-C03-4].