Jacob Fleischmann, M.D.
First of
all, I would like to thank the Shaare Zedek Medical Center
for allowing me to come to Eretz Yisroel and participate in this conference
and, of course, to the committee for selecting me. Just to give you the
appropriate background, my interests are not primarily as a retrovirologist. My
laboratory research interests are related much more to things that I can see
under the microscope like fungi and protozoa and especially as to how they
interact with human host defense cells. However, originally when I decided to
become an infectious disease expert, one of the reasons that I chose this
subspecialty is that this is one area in medicine where you can do something
for the patient. You can cure the patient. I didn’t want to deal with something
like oncology, hematology. And then in 1981 a little event happened and my life
has never been the same ever since. Before I go any further, I need to
apologize to the audience for the following reason. First of all, they gave me
40 minutes to discuss whatever has happened to AIDS since its beginning, an
impossible task. Number two, what makes this topic and this particular talk
very difficult for me is the range of the audience. In this audience there are,
I’m sure, experts at the molecular level all the way to people who have really
very little contact with this virus either in the test tube or in the patient,
and their understanding of this disease is on the level of the layperson. I
will attempt to make at least parts of this talk available to everyone. Thus,
those of you who are molecular biologists, cellular biologists and great
clinicians, my apologies to you if the material that I’m presenting is already
very familiar to you. And to those of you who are perhaps not familiar with the
many aspects of AIDS and some of the material is a little bit beyond you, I
also ask from you Mechilah.
While serological evidence dates AIDS back
to the fifties,[1],[2] the first five
recognized cases were reported by UCLA faculty.[3],[4] At the time I was
an infectious diseases fellow at UCLA and consulted on one of these patients.
He was a perfectly healthy male model commuting between Los Angeles and Paris,
sent over to us from Cedars-Sinai Hospital where he presented with pain on
swallowing. He was found to have thrush in his mouth, and his barium swallow
looked like candida esophagitis. My review of the literature at the time ties
this event to Maimonides Hospital. The definitive paper on candida esophagitis
at that time was in the Journal of Gastroenterology in 1976, published by Dr.
Baruch Kodsi et al.[5]
from Maimonides Medical Center. The paper pointed out two important things.
Candida esophagitis never happens in healthy people, number one. Number two, to
prove the diagnosis, you really have to do a biopsy to show invading hyphal
elements of the fungus. So I managed to convince my attending at UCLA to do a
biopsy on this patient. And lo and behold, the biopsy came back showing no
invasive fungal disease but with evidence for cytomegalovirus (CMV)
esophagitis. Now we knew that CMV is another pathogen causing significant illness
in immunocompro- mised
patients. A couple of weeks later he came back with infiltrates in his lungs,
and because of our previous experience we went for a biopsy early and to our
astonishment it came back positive for pneumocystis carinii (PCP). We used to
see at UCLA prior to AIDS about 5 or 6 cases of PCP per year in our leukemics, but not in apparent normal hosts. At that
moment, I said to my attending, I don’t know what’s going on with this person,
but something is wrong with his immune system. Well, a little bit of a history.
Though
the initial cases reported were from UCLA, we do have serological data going
back at least into the 50’s in Africa. That it was not recognized is not
surprising since there are many wasting diseases on that continent. For example,
a disease known for many years as “slim disease” in Africa, is now known to be
caused by HIV. In the United States it didn’t take us more than a few months to
realize that we were dealing with something very new. Table 1 lists some of the
historical highlights related to this
Table 1 – Brief History of HIV
|
1959
- Retrospective study of sera positive
for HIV in Africa 1968 - A 14 year old male dies in St. Louis, USA,
studies of his frozen tissues find HIV 1981
- First cases officially reported by
UCLA faculty 1982
- First 1000 cases reported in US 1983
- Etiologic virus discovered, later
named HIV 1985 - First 10,000 cases reported in US
Serological test becomes available 1986
- AZT found to be beneficial 1989
- First 100,000 cases reported in US 1991
- First 100,000 deaths reported in US First 200,000 cases reported
in US 1992
- Low CD4 cell counts without HIV
reported First 250,000 cases reported
in US First 170,000 deaths reported
in US |
disease. Among the more mysterious cases is the 14 year old in St. Louis, without travel or risk factors, who died in 1968. One can also see the exploding nature of this epidemic. It took from 1981 to 1985 to diagnose the first 10,000 cases in the US.[6]
Table 2 – Estimated number of HIV cases by region as of
mid – 1993
|
Western Europe Eastern Europe and Central Asia East Asia and Pacific South and Southeast Asia Australia North Africa and Middle East Sub-Saharan Africa North America Latin America and the Caribbean |
500,000 50,000 >25,000 >1,500,000 >25,000 >75,000 >8,000,000 >1,000,000 1,500,000 |
Over the next four years we reached 100,000.[7] It took only two years
to double this number.[8] Table 2 shows the current
estimates of HIV infections worldwide as of
mid 1993.[9] It
is clearly a worldwide epidemic with sub-Saharan Africa being the most
devastated area. I understand there are about 200 cases so far here in
Israel.
A decade of experience with this disease has
established the modes of transmission of HIV and these are listed in Table 3.[10] For adults the two
main routes are parenteral and sexual pointing out the importance of human
behavior in the spread of this disease. Even per- inatal
spread is tied to behavior as the great
majority of children infected are born to HIV infected mothers who are drug
users. Casual and even close personal (but not sexual) contacts such as exists
in the household, workplace or school, are not a risk for transmission. Insects
have been investigated as potential vectors and to this date there is no
evidence that they are.[11]
Breast feeding during the post-partum period can transmit HIV[12]
indicating that oral or gastrointestinal mucosa may be a portal of entry for
the virus. This has halachic implications for a Mohel
who has to do metzitza. A
variety of unusual transmissions have been reported. Some, like organ
transplantation[13]
and artificial insemination[14]
are predictable. Transmission via oral sex has occurred[15]
again pointing to the oral mucosa as a portal of infection. Female to female
transmission has been reported but is rare.[16]
Infection through a bite is not surprising as exchange of blood is likely to
occur.[17]
One report of a wife becoming infected after kissing an impotent HIV positive
husband[18]
turned out to be incorrect.[19]
The well known case of an HIV positive dentist in Florida infecting several of
his patients needs a comment.[20]
The CDC has traced his patient’s isolates to him using DNA sequencing analysis.
Assuming that this is correct, we need to consider that neither before nor
since has there been a case of a dentist infecting a patient. When an extremely
rare event occurs with the same source several times clearly something unusual
had to happen. We do not know what this was. There is one
group referred to by the CDC as having no identifiable risk (NIR).10 Those of us dealing with this disease are
aware of the difficulty in obtaining accurate histories of risk factors, but
the most puzzling among this group are the pediatric cases.
Table 3 – Transmission of HIV
|
Parenteral Sexual Perinatal |
The distribution of
risk factors varies geographically.9 In
the US and Europe it is still predominantly homosexual activity and intravenous
drug use. In the US though the fastest growing group may be the heterosexuals,
especially teenagers. In Africa it is predominantly a heterosexual disease.
This may be partly due to associated sexually transmitted diseases which cause
breakdown of the mucosa enhancing viral transmission.10
Other factors post- ulated have been cervical ectopia
and intercourse during men- struation. Risks associated
with specific activities are not easy to quantify. Table 4 lists the USA and
European experience.10,[21]
Recently there has been a tendency in the lay press to play down the risk of
female to male transmission. While it is clearly less than male to female,
nonetheless it is real. Blood, when properly pro- cessed
is quite safe, though the risk is not yet zero.
Table 4 – Transmission Risks (USA &
Europe)
|
Male to female: |
10 - 20% |
||
|
Female to male: |
1 - 12% |
||
|
Perinatal: |
13 - 33% |
||
|
Healthcare worker needle exposure: |
3 - 5 per 1000
episodes |
||
|
Transfusion: |
1 in 40,000 -
150,000 or less |
||
Table 5 – AIDS in Africa
|
HIV-1 and HIV-2 Heterosexual
transmission 80% (of total) Perinatal transmission
10% (of total) Blood
transfusion 10% (of total) |
Table 5 summarizes
the African experience.[22] HIV-2
is seen primarily in Africa and in those who have traveled there. The blood
supply is still seriously tainted on that continent. One fact which might be
inter- esting to this audience is that circumcision
seems to decrease the rate of transmission but by no means is it 100%
protective.[23]
Table
6 – Isolation of HIV from
body fluids and cells
|
Plasma Peripheral
mononuclear cells Bronchial fluid Tears Ear secretions Saliva Urine Vaginal and
cervical secretions Semen Milk Cerebrospinal
fluid |
Table 6 lists the bodily fluids from which
HIV has been isolated. The virus might be free in fluid or within lymphocytes. Exper- ience has shown us that
the mere presence of the virus in a fluid does not make it a vehicle for
transmission. For example, as we have already mentioned routine kissing is not
a risk but the CDC does recommend against kissing with high negative pressure
in the oral cavity which might lead to bleeding.[24]
The incubation period for the development of
AIDS varies with age.21 Children
infected by transfusion before the age of five have an incubation period of
less than two years. Adults have an incubation period from eight to ten years.
When looking at the distribution of disease by age, one sees the truly
devastating aspect of this disease as it primarily hits young adults. Recently,
the press has focused on long term infected individuals who have not developed
AIDS. The actual data is as follows; so far about 60% of infected individuals
have developed AIDS.9 Furthermore, mathematical models are
predicting that close to 100% eventually will.[25]
Thus long-term survivors, and now some of them are going beyond 12 years,
probably represent just the edge of the bell- shaped curve. Clearly this
retrovirus does not behave like HTLV-1 where only perhaps 10% of the people who
are infected will come down with leukemia or the other manifestations of that
virus.[26]
Now about the virus itself. We probably have
accumulated more information about HIV than any other human viral pathogen. I
will highlight only the main features.[27]
Similar to other retroviruses it has within a host derived lipid bilayer, core
proteins surrounding the genomic RNA. Protruding through the lipid bilayer are
rod and sphere shaped envelope proteins. Working our way from the core to the
surface we first encounter two identical genomic RNAs making this virus
diploid. With them are two enzymes necessary for replication and integration,
namely reverse transcriptase (RT) and integrase. Surrounding them is the core
protein of which p24 is the major component and just inside the lipid bilayer
is the matrix containing p17. Protruding through the bilayer are glycoproteins
gp120 and gp41. At the genomic level it has the standard retroviral structural
genes: gag which encodes the proteins that form the
virion core; pol which encodes for reverse transcriptase
integrase and protease; env which encodes the envelope glycoproteins.
In addition it has several overlapping open reading frames containing several
regulatory and accessory genes. These include tat, rev, nef, vif, vpr, and
vpu for HIV-1 and vpx
for HIV-2. Deletion analysis has given us some insight into the function of
these genes but we have a long way to go in fully understanding their
activities. Tat and rev are essential for
the optimal transcription and translation of structural gene products. Nef appears to maintain latent infection. Vif
appears to be necessary for infectivity and Vpu for
the release of budding virions from the surface of infected cells. Flanking
these genes are long terminal repeats (LTRs) which contain regulatory elements
involved in gene expression.
A simplified version of the life cycle of
HIV is as follows:[28]
the virus via its GP120 molecule attaches itself to a CD4 receptors on cells.
GP41 facilitates entry of the virus into the cell by fusing with the target
cell membrane. There is some data which suggest that the virus might gain entry
into the cell via other routes: for example, being part of a antigen-antibody
complex, and entering cells via Fc receptors. There is also data that for some
neural and epithelial cells the galactosyl ceramide molecule may function as a
receptor. Once endocytosed, the uncoated viral single stranded RNA is
transcribed into double stranded DNA (provirus) by reverse transcriptase. It is
the infidelity of RT that allows frequent mutations leading to variations in
isolates making it more difficult for the immune system to handle this virus.
The provirus enters the cell nucleus and integrates into the host genome. This
is one of the critical features one needs to contemplate when thinking about
cure, as these cells are permanently transformed. Under certain conditions, the
provirus is transcribed, giving rise to viral RNA, coding for viral proteins
which ultimately get assembled to make complete virions. These progeny are
released by budding from the cell membrane.
Table 7 shows a variety of cells susceptible
to HIV infection at least in vitro.[29],9
Some of these, such as fibroblasts appear to lack CD4 receptors again
suggesting that the virus can be internalized by other means. What direct
effect on cellular and ultimately organ function this has is not fully
understood. For example, a number of papers have been published looking at
macrophage function after in vitro HIV infec- tion and the results are con- flicting.
Overall, macrophage fun- ction, at least as studied
in vitro, does not seem to be severely impaired. In vivo these cells have been
suspected as reservoirs for viral replication and dissemination. A variety of
functional abnormalities have been reported for other cells of the immune system
from HIV infected individuals. B lymphocytes are generally activated leading to
hypergammaglobulinemia, circulating antigen-immune complexes and
autoantibodies. These patients also respond poorly to vaccines and have
increased incidence of infections with capsular bacteria. Natural killer cells,
while not targets for HIV, have decreased surveillance activity.
Table 7 – Cells susceptible for HIV
|
T and B Lymphocytes |
Bowel
epithelium |
|
Macrophages |
Renal
epithelium |
|
Promyelocytes |
Langerhans
cells |
|
Dendritic cells |
Fibroblasts |
|
Astrocytes |
Enterochromaffin
cells |
|
Oligodendrocytes |
Cervical
cells |
|
Capillary endothelium |
Megakaryocytes |
|
Cardiac myocytes |
Trophoblastic
cells |
Table 8 – Possible
mechanisms of
lymphocyte impairment by HIV
|
Direct Cytopathy Lysis Syncytia
formation |
|
Indirect Mechanisms Apoptosis Autoimmune Superantigen |
|
Cofactors CMV, mycoplasma, EBV, etc. |
The pivotal cells involved in immune
suppression in HIV are the T-lymphocytes. While a number of qualitative
deficiencies have been described for these cells, it is their ultimate
depletion that leads to end stage disease. These deficiencies include impaired
expression IL-2 receptors, decreased IL-2 and interferon-gamma production38 and impaired
helper function for B-lymphocytes to produce immunoglobulin. Table 8 lists
possible mechanisms which either destroy or disarm T-lymphocytes.28 Some destroy
the cells directly, such as lysis and syncytia formation. A more controlled
destruction involves apoptosis which represents
genetically programmed death of cells.[30] As
part of normal physiology, this process eliminates T-lymphocytes capable of
recognizing self-antigens. There is in-vitro evidence that the interaction of
GP-120 with the CD4 receptor can trigger this process. Another mechanism
postulated is autoimmunity. Since MHC class II products share some homology
with GP-120 and GP-41 proteins, autoantibodies might be generated by HIV
infection reacting with T-lymphocytes. Finally, some antigens can interact with
a less specific portion of the beta chain of the T-cell receptor leading to
anergy or deletion of a large number of T-lymphocytes. Such antigens are
referred to as superantigens, and there is some data suggesting their
presence in HIV infected patients. Finally, coinfection with other viruses like
CMV or EBV may play a role in immune destruction. Recently a mycoplasma has
been touted for such a role, but none of this is proven.
What happens to these patients clinically?
Studies on patients diagnosed with their initial infection[31]
show significant plasma viremia which declines to almost undetectable levels
after the appearance of HIV antibodies. This period has been referred to as
latency.
As full blown AIDS develops and CD4 positive
T-lymphocytes decline, the virus reappears and increases as the patient dies.
P-24 antigens shows the same pattern. The latent period during which only a
small fraction of the circulating T-lymphocytes are found to be HIV infected
has been puzzling. Recent data, however, has begun to elucidate what really
happens.[32],[33]
Investigators using quantitative PCR and in-situ hybridization techniques have
shown that active multiplication of HIV and systematic infection of
T-lymphocytes continues in lymph nodes. The cell that plays a central role in
this process is the follicular dendritic cell (FDC) which traps and presents
HIV to T-lymphocytes. Ultimately, these cells die and on electron microscopy
one can see the destruction of the architecture of the lymph nodes leading to a
decrease of CD4+ cells. With the increasing viral burden, spillover into the circu- latory system occurs
leading to increasing viremia. It is at this point when the patient becomes the
target of a number of opportunistic infections.
Thus, while there may be a clinical latency,
microbiologically the process is ongoing and unrelenting.
Table 9 – Testing
for HIV infection
|
Viral Culture Antibody tests Elisa Western Blot Radioimmunoprecipitation Indirect
immunofluorescence p24 antigen PCR |
The case definition of AIDS has been
expanded by the CDC to include patients with CD4+ T-lymphocyte count of less
than 200/mm3.[34]
Also added were pulmonary tuberculosis, recurrent bacterial pneumonia, and
invasive cervical carcinoma. The pre- vious criteria
otherwise remains the same. The clinical class- ification
system developed by the CDC is based on a combination of CD4+ T cell count and
clinical categories using a numerical and alphabetical combination. CD4+ T cell
counts of >500/mm3=1; 200-499/mm3=2; 200/mm3=3.
Asymptomatic, persistent general- ized
lymphadenopathy, acute HIV infection are in category A; symptomatic but not
AIDS in category B; and AIDS is category C. This classification system allows
us to compare efficacy of clinical trials.
Table 9 lists the tests avail- able to
detect HIV infection.[35]
The primary way we diagnose this disease is by looking for anti- bodies. The
ELISA test is most commonly used today, and has a specificity and sensitivity
close to 99%. Each positive ELISA is still confirmed with a Western Blot. Viral
cultures which can be done quantitatively are tedious and they are mostly used
in research laboratories. The p24 antigen assay is only useful in early or late
infection and is not useful as a screening test. PCR, when done carefully, can
detect very low viral loads within hours, but false amplifications can lead to
unnecessary anxiety. It is commercially available, but one needs to know the
quality of the laboratory doing it.
A variety of prognostic markers have been
described in the literature, including neopterin, and beta2 microglobulin.[36]
Clinically, our most useful marker is the CD4+ T cell count. Table 10 lists the
complications related to declining CD4+ T cell counts. In addition to knocking
out the immune system, HIV can cause complications with many other systems.
Time does not permit me a detailed description and I will highlight only a few.21 The most common skin manifestations are
seborrheic dermatitis and acne-like lesions. Oral manifestations include thrush
and hairy leukoplakia.
Table 10 – CD4+ T cell counts & complications
|
500-250: |
Candidiais,
Tuberculosis |
|
200-150: |
KS,
PCP, lymphoma, cryptosporidia |
|
125-75: |
MAI, HSV, toxoplasmosis, cryptococcosis,
esophageal candida |
|
50: |
CMV retinitis |
Neurologically we most commonly see AIDS dementia
and peripheral neuropathies. Intractable diarrhea from a variety of causes can
be devastating to these patients. Hematologically,
almost any cell line in the bone marrow can be suppressed. Idiopathic thrombocytopenic
purpura is not unusual and will frequently respond to high dose AZT therapy.
These patients can develop pericardial effusions which occasionally lead to
tam- ponade. Of the endocrine system, it is the
adrenal gland that is most commonly involved with adrenalitis, but clinical
adrenal insufficiency is unusual. Focal and segmental glomerulosclerosis (FSGS)
of the kidneys frequently leads to end stage renal disease. A variety of
disorders might involve the musculoskeletal system and these include arthritis,
polymyositis and vasculitis. Malign- ancies include
Kaposi’s sarcoma and non-Hodgkin’s lymphoma.
You are familiar with a long list of
opportunistic infections these patients are susceptible to.21 I will just highlight a few of the more
interesting questions related to infections. While atypical mycobacteria like
MAI cannot be treated, and most fungal infections require lifelong therapy, why
is it that tuberculosis can be successfully treated? Incidentally, a most
serious complication is the development of multiple drug resistant tuberculosis
among these patients which can potentially infect HIV negative population, too.
Why is it that intracellular pathogens like listeria monocytogenes and
legionella pneumophila do not have an increased incidence among HIV patients?
While one of the most common clinical manifestations of HIV infection is
thrush, we see very little invasive candidiasis in these patients.
Table 11 – Therapy
of HIV Infection
|
Antiretroviral Treatment of opportunistic infections Prophylaxis of opportunistic infections Treatment of malignancies |
Table 11 lists our therapeutic approach to
these patients.[37]
AZT has been shown to delay the onset of AIDS, however it remains controversial
if it prolongs survival. Our capacity to keep these patients alive longer is
mostly related to our aggressive treatment of such opportunistic infections as
PCP and prophylactics against them. Treatment of malignancies remains dismal.
Vaccines which have so far been tested on humans have been disappointing.[38][39]
The most promising vaccine so far appears to be one where the nef gene has been deleted from SIV and this has
been 100% protective against the complete virus in monkeys. Future approaches
to therapy include every step of viral-cellular interaction, from initial
attachment to release and maturing of virions.[40] As
our understanding at the molecular level increases so will likely our
therapeutic armament.
While the overall picture may appear to be bleak, in fact, we have all the knowledge and the technical capacity to stop this epidemic in its tracks. The one variable which we can not control is human behavior. This is an important point to contemplate at a conference on Ethics and Halacha.
Source: ASSIA – Jewish Medical Ethics,
Vol. II, No. 2, May 1995, pp. 3-9
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