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INFECTIOUS DISEASE

BACTERIOLOGY IMMUNOLOGY MYCOLOGY PARASITOLOGY VIROLOGY

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VIROLOGY - CHAPTER   SEVEN    

PART THREE

HUMAN IMMUNODEFICIENCY VIRUS AND AIDS  

THE COURSE OF THE DISEASE

Dr Richard Hunt
 

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hiv time course.jpg (46994 bytes)  Virus titer, CD4 cell number and anti-gp120 titer during the course of HIV infection

hiv time course2.jpg (43312 bytes) Virus titer, CD4  and CD8 cell number  during the course of HIV infection

Figure 4

From the original infection, there is usually a period of 8 to 10 years before the clinical manifestations of AIDS occur; however, this period may be two years or less. Approximately 10% of patients succumb to AIDS within 2 to 3 years.
 

Acute infection (acute retroviral syndrome)

This period lasts for 6 to 12  weeks after initial infection until anti-HIV antibodies are detectable.

If acquired by sexual activity, the virus enters the body in infected macrophages in semen or vaginal secretions. Dendritic cells in the mucosal linings bind the virus shed by macrophages and carry it to the lymph nodes where CD4+ T4 cells become infected. During the course of the disease, the virus migrates to other cell types.

Initially, HIV infection produces a mild disease that is self-limiting. This is not seen in all patients and about 30% remain asymptomatic during the initial period of infection. In the period immediately after infection, virus titer rises (about 4 to 11 days after infection) and continues at a high level over a period of a few weeks (figure 4). The patient often experiences some mononucleosis-like symptoms (fever, rash, swollen lymph glands) but none of these is life-threatening. There is an initial fall in the number of CD4+ cells and a rise in CD8+ cells but they quickly return to near normal. At this stage virus titers are very high with as many as one hundred million virus particles per milliliter of plasma.

During the first two weeks of infection two weeks, CD4+ cells in the lymphoid tissue if the alimentary tract decline. This has two results: Local immunodeficiency and chronic immune activation. Immune activation results from translocation of bacteria across the damage mucosa of the alimentary tract.

There is a "window period" of seronegativity during which an infected person does not give a positive western blot HIV test or ELISA, even though the viral load is high and the patient may exhibit some symptoms. This seronegative period can last for six months before seroconversion although the latter usually occurs between one and four weeks after infection. 

Early symptoms of HIV infection

 

A strong cell-mediated and humoral anti-HIV immune defense

Cytotoxic B and T lymphocytes mount a strong defense and virus largely disappears from the circulation (figure 4). After the increased cell-mediated immune response, there is a rise in humoral antibodies. During this period of strong immune response to the virus, more than 10 billion new HIV particles are produced each day but they are rapidly cleared by the immune system and have a half life of only 5 to 6 hours (some estimates show a half life of minutes). Although there can be up to 108 virus particles per ml of blood, the number of infectious virus particles is much lower indicating that much of the plasma virus is defective or neutralized. At this stage, most of this virus is coming from recently infected proliferating CD4+ cells (figure 5), including HIV-specific CD4+ cells. Thus, the virus is destroying the very cells that are proliferating to protect against it. The infected cells that are producing this virus are destroyed either by the immune system or by the virus  and have a half life about 1 day. However, the rate of production of CD4+ cells can compensate for the loss of cells and a steady state is set up in which most CD4+ cells are uninfected.

Although activated, proliferating CD4+ cells are destroyed by the immune system, a small fraction of the infected cells survive long enough to revert back to the resting memory state (as do non-infected CD4+ memory cells). The resting memory cells (also referred to as anamnestic T cells) do not express viral antigens but do carry a copy of the HIV genome which remains latent until the cells are reactivated by antigen. These memory cells may survive many years and constitute a reservoir that is very important in drug-based therapy. 

During this period, the virus disseminates to other regions including to lymphoid and nervous tissue. This is the most infectious phase of the disease.

More on the immune response

 

A latent reservoir

As a result of the strong  immune defense, the number of viral particles in the blood stream declines and the patient enters clinical latency (figure 4). Little virus can now be found in the bloodstream or in peripheral blood lymphocytes and, initially, the number of blood CD4+ cells is only slightly decreased.  Nevertheless, the virus persists elsewhere, particularly in lymph nodes and here viral replication continues as follicular dendritic cells interact with more CD4+ cells that become infected.  The virus is also replicated by macrophages.

Although the number of HIV particles in the bloodstream is much reduced during clinical latency, the virus is detectable. After the initial peak of virus, the virus reaches a "set point" during latency. This set point predicts the time of onset of clinical disease.  With less than 1000 copies/ml of blood, disease will probably occur with a latency period of more than 10 years.  With less than 200 copies/ml, disease does not appear to occur at all. Most patients with more than 100,000 copies per ml, lose their CD4+ cells more rapidly and progress to AIDS before 10 years. Most untreated patients have between 10,000 and 100,000 copies per ml in the clinical latency phase (See below).

 

Loss of CD4+ cells and collapse of the immune response

One reason that the immune system fails to control HIV infection is that the CD4+ T helper cells are the target of the virus. Also follicular dendritic cells can be infected with HIV and these also diminish in number over time. Moreover, dendritic cells present antigen to CD4+ cells and may bring the virus into contact with these cells at the time that they are stimulated to proliferate by antigen.

During the course of infection, there is a profound loss of the specific immune response to HIV because:

  • responding CD4+ cells become infected. Thus, there is clonal deletion leading to tolerance. The cells that proliferate to respond to the virus are infected and killed by it

  • epitope variation (see below) can lead to escape of HIV from the immune response

  • activated CD4+ T cells are susceptible to apoptosis. Spontaneous apoptosis of uninfected CD4+ and CD8+ T cells occurs in HIV-infected patients. Also there appears to be selective apoptosis of HIV-specific CD8+ cells

  • the number of follicular dendritic cells falls over time, resulting in diminished capacity to stimulate CD4+ cells

There is thus a relentless decline of CD4+ cells with especially a loss of those specific to HIV. This occurs from the very beginning of infection and is permanent (unless chemotherapy intervenes). Near the end stage of AIDS, CD8+ cells also decline precipitously. It is nevertheless the case that during the course of HIV infection, most CD4+ cells are never actually infected by the virus but die from some other means (see below).

 

Onset of disease - AIDS

The period of clinical latency varies in length from as little as 1 to 2 years to more than 15 years. Onset of AIDS  is rare in less than 3 years except in children. But, eventually, the virus can no longer be controlled as helper CD4+ (T4) cells are destroyed (figure 4). Ironically, the killer cells needed to control HIV also damage the helper T cells that they need to function efficiently. With the lack of CD4+ cells, new cytotoxic T cell responses cannot occur as helper cells are lacking and such new responses are required as the virus mutates. As the CD4+ cells fall below 200 per cu mm, virus titers rise rapidly and immune activity drops precipitously. It is the loss of immune competence that enables normally benign opportunistic parasites such as viruses, fungi or protozoa to cause infections (figure 6A and B). Once AIDS develops, patients rarely survive more than two years without chemotherapeutic intervention. (See anti-HIV chemotherapy chapter). There is considerable variability at this stage. Some patients with clinical AIDS do survive for several years while others who appear relatively healthy can suddenly succumb to a major opportunistic infection.  It is the onset of HIV-associated cancers and opportunistic infections that defines AIDS proper. At this stage, also, syncytium-inducing HIV appear in many (about half) AIDS patients (see below). These are more CD4+ cell tropic than the initially infecting HIV and this contributes to the rapid loss of CD4+ cells in later stages of the disease.

 

AIDS-defining diseases WHO staging of AIDS disease Diseases associated with levels of CD4 cells during HIV infection Can CD8+ cells be infected by HIV?

It should be noted that a phase of HIV infection, AIDS-related complex (ARC), used to be defined. This is now little used. It is the phase of the disease that lacks the neoplasms and opportunistic infections that are the definition of AIDS. Patients at this stage of the disease show weight loss and fatigue together with fungal infections of the mouth, finger and toe nails.

 

 
hivbud2.jpg (75738 bytes) HIV-1 budding from cultured lymphocyte. Transmission electron micrograph.  CDC/Dr. Edwin P. Ewing, Jr.  epe1@cdc.gov 

scan em.jpg (107122 bytes) Scanning electron micrograph of HIV-1 budding from cultured lymphocyte. Multiple round bumps on cell surface represent sites of assembly and budding of virions (CDC)

Figure 5

WEB RESOURCES

CDC Guidelines for National Human Immunodeficiency Virus Case Surveillance, Including Monitoring for Human Immunodeficiency Virus Infection and Acquired Immunodeficiency Syndrome

Figure 6A
The natural history of an HIV infection. Opportunistic infections during the course of the disease
 

 

 

 

 

Figure 6B - AIDS related diseases


pneuomcyst.jpg (118755 bytes) Cysts of Pneumocystis carinii (Pneumocystis jiroveci) in AIDS. Methenamine silver stain. Histopathology of lung shows characteristic cysts with cup forms and dot-like cyst wall thickenings. CDC/Dr. Edwin P. Ewing, Jr. epe1@cdc.gov 

hairy tongue.gif (58131 bytes) Hairy leukoplakia of tongue in AIDS Bristol Biomedical Image Archive, University of Bristol. Used with permission

cryptococcus.jpg (99057 bytes) Cryptococcosis of lung in patient with AIDS. Methenamine silver stain. Histopathology of lung shows numerous extracellular yeasts of Cryptococcus neoformans within an alveolar space. Yeasts show narrow-base budding and characteristic variation in size. CDC/Dr. Edwin P. Ewing, Jr. epe1@cdc.gov

thrush.jpg (60483 bytes) Oral thrush. CDC 

candida.gif (34953 bytes) Candida and herpes simplex in AIDS  Bristol Biomedical Image Archive, University of Bristol. Used with permission

cat scratch.jpg (243193 bytes) Cat-scratch disease involving parotid lymph node in AIDS   Bristol Biomedical Image Archive, University of Bristol. Used with permission

chelitis.gif (66994 bytes) Severe angular cheilitis in AIDS   Bristol Biomedical Image Archive, University of Bristol. Used with permission

granula.jpg (436920 bytes) Orofacial granulomatosis with cobble stone mucosa in AIDS   Bristol Biomedical Image Archive, University of Bristol. Used with permission

facial-sarc-hiv.jpg (317042 bytes) Facial sarcoidosis in AIDS  Bristol Biomedical Image Archive, University of Bristol. Used with permission
 
 
rate.jpg (74646 bytes) Rate of progression to AIDS associated with homosexuality and hemophilia
HIV-HS: HIV negative homosexual.
HIV+ HS: HIV positive homosexual

Figure 7 

 

 


 

Despite possible co-factors associated with lifestyle, HIV infected persons progress to AIDS at a similar rate

The mean time from seroconversion to onset of disease is approximately 9 years (figure 7). The time is similar whether the virus was acquired by sexual behavior or the use of clotting agents. Perinatally-infected infants progress faster. Signs of AIDS can be seen by 5 months in more than 80% of seropositive children. About half die by nine years of age. In neonates, the level of viral RNA rises rapidly in the first few months of life but does not decline as rapidly as is seen in adults.  The decline that occurs takes place over a period of a year or more. This presumably reflects the less effective infant immune system. As in adults, the level of HIV RNA predicts the rapidity of  progression to AIDS. 

There are a variety of factors that determine progression of an HIV infection to clinical AIDS disease

Factors that determine progression to AIDS

AIDS in neonates


 

HIV load but not CD4+ T cell number is a good indicator of rapid progression to AIDS

The onset of AIDS occurs, on average, about 9 years after infection but in the absence of treatment some individuals progress much faster. About 20% of patients exhibit AIDS symptoms within 5 years of infection while others remain disease free much longer than average. The onset of AIDS correlates with the diminution of the number of CD4+ T cells but the major loss of T cells occurs late in infection. A marker that could predict the prognosis for AIDS progression early in the disease would be useful. Not surprisingly, the initial baseline viral load (that is when the patient is first monitored for virus number) is a good predictor of the time it will take for disease to appear. CD4 cell number is not a good predictor until late in the course of infection (figure 8).

 

Figure 8 - Predictors of progression to AIDS

 

aids-1.jpg (63251 bytes)  Figure 8A  Relationship  between baseline viral load and progression to AIDS.   For quartiles from the lowest to the highest viral load at time of entry into the study, the percentages of patients that progressed to AIDS in 5 years were 8, 26, 49 and 62 (data from Mellors et al. Science 272: 1167-1170)   

aids-2.jpg (81524 bytes) Figure 8B  Relationship between baseline viral load and median survival time. The median time for the patients in each of these viral load categories was more than 10 years, 7.7 years, 5.3 years and 3.5 years

aids-3.jpg (67254 bytes) Figure 8C   Relationship between baseline CD4+ T cell number and progression to AIDS. With the exception of patients who entered the study with less than 321 CD4+ cells per microliter of blood, no difference was found in either the time of disease onset or the time of death among patients with CD4+ cell counts of 322 to more than 787.
 

 


OTHER SECTIONS ON HIV

PART I HUMAN IMMUNODEFICIENCY VIRUS AND AIDS

PART II HIV AND AIDS, THE DISEASE

PART III COURSE OF THE DISEASE

PART IV  COFACTORS

PART V STATISTICS

PART VI  SUBTYPES AND CO-RECEPTORS

PART VII  COMPONENTS AND LIFE CYCLE OF HIV

PART VIII  LATENCY OF HIV

PART IX GENOME OF HIV

PART X  LOSS OF CD4 CELLS

PART XI   POPULATION POLYMORPHISM

APPENDIX I  ANTI-HIV VACCINES

APPENDIX II  DOES HIV CAUSE AIDS?

APPENDIX III  ANTI-HIV CHEMOTHERAPY

 

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