Primary HIV Infection, and the Immune Response

the First National Conference on Human Retroviruses and
Related Infections. The first part appeared in issue #190.]

With about 40 thousand new HIV infections per year in the
United States, the domestic AIDS epidemic is hardly over. Yet
until now little attention has been devoted to finding those
who are newly infected, or to finding prompt treatment
regimens that might attenuate the course of their disease.

Part of the difficulty is detecting HIV infection at its
earliest point, since people usually have only mild or vague
flu-like symptoms when they first contract the virus. (This
initial period of symptomatic HIV infection is known as
"acute" or "primary" infection. The chronic period of
infection occurs after the original symptoms disappear and
the slowly progressing disease process takes over.)

Primary HIV infection is hard to diagnose because the
standard HIV blood test does not detect the virus directly.
Instead, this test only checks for antibodies produced by the
body in response to HIV. It is worthless for uncovering new
infections, since antibodies to HIV appear some weeks or
months after transmission takes place.

The First National Conference on Human Retroviruses and
Related Infections, last month in Washington, D.C., brought
together some of the researchers who are studying primary
infection. The result was a broad discussion of some of the
great unanswered questions concerning what increasingly
appears to be a critical time in the development of AIDS.

George Shaw, M.D., of the University of Alabama, indicated
the nature of the problem: In a 1989 survey of 2300 emergency
room visitors at Baltimore's Johns Hopkins Hospital, 180
patients were HIV-positive by the standard HIV antibody test.
But there were six patients with unsuspected HIV who tested
negative on the antibody test but positive on a direct test
for HIV -- the test that looks for HIV core (or "p24")
proteins in a person's blood. Dr. Shaw estimated that Johns
Hopkins, a hospital with a great deal of AIDS consciousness
due to its location, may see 70 to 115 patients a year with
undetected primary HIV.

Dr. Shaw has followed six patients at his home hospital in
Birmingham, Alabama who came in with serious acute HIV
infections. They were very ill for two weeks, exhibiting a
wide array of symptoms, from rashes and swollen lymph glands
to liver and neural dysfunctions. In every case the symptoms
cleared up spontaneously within two weeks, and the six
started producing antibodies to HIV a month later. Their
histories diverged after that; one has maintained a normal T-
helper cell count for the past three years while two others
saw their T-helper cell counts drop precipitously to the
levels associated with AIDS in the year after contracting
HIV.

(Note that those who are sick enough during primary infection
to seek medical attention may not at all be representative of
others who never come to the attention of researchers because
their primary infection is mild or even asymptomatic. This is
another problem in studying primary HIV disease.)

The range in response may be due to the type of virus each
person received during transmission. Jaap Goudsmit, M.D., at
the University of Amsterdam noted, though, that his group had
found that less than five percent of acute HIV infections
involved especially virulent viral strains (the so-called
"syncytium-inducing" or SI types). An assessment by
Goudsmit's group of 42 people who contracted a non-SI type of
HIV could find no further predictor of progression. Shortly
after acute infection, neither HIV blood levels, viral
genetic characteristics, nor T-helper cell count, separated
those who developed AIDS in the next four years from those
who were still AIDS-free after six years. But in the three
years after acute infection, HIV levels seemed to go down in
slow progresssors, while remaining stable in faster
progressors, suggesting that the long-term quality of immune
defenses is the crucial factor in the speed of AIDS onset.

David Ho, M.D., of the Aaron Diamond AIDS Research Center in
New York, confirmed that highly virulent SI viral varieties
hardly ever seem to get transmitted. His lab analyzed the
virus found in 20 men with new HIV infections, all contracted
sexually. When trying to culture this virus, researchers
noticed that it grows much better in the monocyte-macrophage
type of cell (an immune system sentinel cell that traps
foreign microbes) than in T-helper cells. On the other hand,
the virulent virus which is often found in advanced HIV
infection grows better in T-helper cells.

The virus in newly infected people also is very homogeneous.
Dr. Ho and his collaborators have identified the genetic
sequences of the viral strains in five of the recipients, as
well as the people they received HIV from. Each recipient's
HIV varied little in its genetic makeup, whereas the HIV in
each donor (all asymptomatic men) exhibited a large degree of
genetic diversity. A great deal of mutation clearly takes
place after infection, as HIV adapts to its new host.

The virus present during the acute infection seems to be a
minor variant present in small numbers in the donor. The
variant can be found in the cells (probably monocytes or
other immune cells) present in the donor's semen and to a
lesser extent in the seminal fluid (and sometimes not at
all). It cannot be detected in the cells or plasma of the
blood. (This suggests that the forms of HIV which are readily
transmitted are not highly pathogenic (disease causing) by
themselves. But HIV mutates very rapidly, forming many
different variants, some of which are highly pathogenic.)

Dr. Ho noted that these findings have serious implications
for vaccine research, which has concentrated on laboratory
strains of HIV grown in T-helper cells. This is a variety
with properties considerably different from the type of HIV
that seems most transmissible. In future vaccine
investigations, "we need to target transmitted virus, not
those highly adapted to T-cell lines," Dr. Ho said.

When HIV first enters the body, it can cause abrupt illness
because there is no immune response that specifically targets
the virus. Even before antibody production begins, though,
most of the HIV present in the bloodstream has disappeared.
Richard Koup, one of Dr. Ho's colleagues at the Aaron Diamond
Center, described his group's analysis of how immune defenses
against HIV unfolded after transmission in five patients. (In
only two of these are samples available from the period
before antibody production began.)

Dr. Koup's observations indicated that cytotoxic T-
lymphocytes (CTLs), designed to hunt out and kill HIV-
infected cells, are the first HIV-specific immune response.
They stem the initial burst of HIV replication. It can take a
year to develop anti-HIV antibodies that can effectively
block the virus from infecting new cells. The one person in
the group who had a sustained, dramatic fall in T-helper cell
count also had a delay in the emergence of anti-HIV CTLs.

This conclusion has considerable implications for vaccine
development. It was supported by a number of other
presentations at the conference. There has been some recent
work, however, that indicates that the CTL and antibody
responses interfere with one another. The first gradually
fails as the second increases. This is the so-called switch
from the Th1 to Th2 immune mode. The Aaron Diamond group
found that the CTL (killer cell) response peaks and then goes
down, but it holds for years. There is considerable overlap
between the two modes.

One of the conventional observations about post-acute
conditions in HIV infection is that viral levels in the blood
are reduced almost to zero. Newer, more sensitive tests, such
as those involving polymerase chain reaction (PCR), confirm
that viral levels do go down by a hundred or a thousand times
after the acute infection ends. This is a greater reduction
than any currently available treatment can accomplish, but
there is still much HIV in the bloodstream. Dr. Shaw wondered
why HIV is usually difficult or impossible to culture from
the blood of infected individuals during this stage.

Meanwhile, the continuing work with lymph nodes, at the
National Institutes of Health and elsewhere, further
documents that during the symptomless post-acute period, HIV
concentrates in these centers of immune activity. The lymph-
node data suggest that use of a drug like AZT, which helps
prevent the infection of new cells, might be most useful
during acute infection. At that point, few cells harbor HIV;
perhaps this number could be kept low, with the lymph nodes
greatly protected. Anthony Fauci, M.D., the director of the
National Institute of Allergy and Infectious Diseases, raised
this possibility in a recent article.(1) Dr. Fauci also
warned of the risk of developing AZT-resistant HIV strains
(which will then be hard to treat later on) and of the drug's
toxic side effects (which may perturb immune system
function).

But a questioner at the Retrovirus Conference wondered
whether using AZT at the first possible moment might lead to
a faster decline. Panelists replied that no data was
available on the risk of accelerating disease progression.

The questioner's concern may have stemmed from a letter from
a research group in Australia which is testing AZT to treat
primary HIV infection.(2) The letter described their
experience treating seven gay men with acute HIV infection.
The seven received a total of one gram of zidovudine a day
for an average of 56 days, and were compared with records of
15 untreated men used as historical controls. After two
months the treated group had half the cytotoxic lymphocyte
and total lymphocyte counts of the untreated group. T-helper
counts were about the same for both groups. The authors
theorized that reducing HIV replication with AZT may dampen
the immune response, especially against the normally more
virulent, "syncytium-inducing" strains. The authors noted
that AZT might also directly suppress CTL (cytotoxic T
lymphocyte) replication. The long-term effects, if any, of
the reduced lymphocyte counts remain to be seen; the letter
only reported the blood work, not symptoms or clinical
condition of the volunteers.

The Australian group suggested that it might be better to use
immune modulators, "such as IL-2 or the interferons," instead
of AZT for treating primary HIV infection -- to promote the
CTL response.

The NIH has an on-going trial to test AZT for primary
infection, but that trial is moving very slowly because of
the difficulty of finding appropriate participants. At
present, only about ten people are enrolled, of the 80
positions which are open.

This trial is being conducted in nine cities: Baltimore,
Chicago, Dallas, Fort Lauderdale, Houston, Los Angeles, New
York City, Palo Alto, and Providence. For information about
enrolling patients who may have primary HIV infection,
physicians should call the AIDS Clinical Trials Information
Service, 800/TRIALS-A.

References

1. Fauci AS. Multifactorial nature of human immunodeficiency
virus disease: Implications for theory. SCIENCE. November 12,
1993; volume 262, pages 1011-1018.

2. Tindall B, Carr A, Goldstein D, Penny R, and Cooper DA.
AIDS. January 1993; volume 7, number 1, pages 127-128.