IV. VIRUSES

F. ANIMAL VIRUS LIFE CYCLES

4. A Natural History of HIV Infection

Fundamental Statements for this Learning Object:

1. The median incubation period for AIDS is around 12 years.
2. During early or acute HIV infection the virus primarily infects and destroys memory T4-lymphocytes which express the chemokine receptor CCR5 and are very abundant in mucosal lymphoid tissues. Here HIV also encounters the dendritic cellslocated throughout the epithelium of the skin and the mucous membranes.
3. The dendritic cells detach from the epithelium, enter lymph vessels, and are carried to regional lymph nodes where they are now able to present antigens of HIV to naive T-lymphocytes in order to induce adaptive immune responses.
4. The virus transitions from the acute phase to the chronic phase characterized by viral dissemination, viremia, and induction of adaptive immune responses.
5. The viremia allows the viruses to spread and infect T4-helper lymphocytes, macrophages, and dendritic cells found in peripheral lymphoid tissues.
6. During the chronic phase of HIV infection, the lymph nodes and the spleen become sites for continuous viral replication and host cell destruction whereby a steady state-infection generally persists where T4-lymphocyte death and T4-lymphocyte replacement by the body are in equilibrium.
7. The enormous turnover of T4-lymphocytes eventually exhausts the lymphopoietic system and it becomes unable to replace the T4-cells being destroyed eventually leading to immunodeficiency.
8. Progression to AIDS is marked by a viral load that progressively increases in number while the immune system weakens as a result of the destruction of increasing numbers of T4-lymphocytes and the inability of the body to continually replace these destroyed cells.
9. As a result of immunosuppression, the person becomes susceptible to a variety of opportunistic infections and secondary cancers.

 

LEARNING OBJECTIVES FOR THIS SECTION

Viruses are infectious agents with both living and nonliving characteristics.

1. Living characteristics of viruses

a. They reproduce at a fantastic rate, but only in living host cells.

b. They can mutate.

2. Nonliving characteristics of viruses

a. They are acellular, that is, they contain no cytoplasm or cellular organelles.

b. They carry out no metabolism on their own and must replicate using the host cell's metabolic machinery. In other words, viruses don't grow and divide. Instead, new viral components are synthesized and assembled within the infected host cell.

c. The vast majority of viruses possess either DNA or RNA but not both.

A Natural History of a Typical HIV Infection

According to WHO, globally, 38.0 million (31.6–44.5 million) people were living with HIV at the end of 2019. An estimated 0.7% (0.6-0.9%) of adults aged 15–49 years worldwide are living with HIV, although the burden of the epidemic continues to vary considerably between countries and regions.  The interval from HIV infection to the diagnosis of AIDS ranges from about 9 months to 20 years or longer.The median incubation period (def) for AIDS is around 12 years. 

During early or acute HIV infection the virus primarily infects and destroys memory T4-lymphocytes which express the chemokine receptor CCR5 and are very abundant in mucosal lymphoid tissues. Here HIV also encounters the dendritic cells (def) located throughout the epithelium of the skin and the mucous membranes where in their immature form called Langerhans cells they are attached by long cytoplasmic processes. The envelope glycoproteins gp41 and gp120 of HIV contain mannose-rich glycans that bind to mannan-binding proteins (pattern recognition receptors; also called lectin receptors) on the dendritic cells.

Upon capturing antigens through pinocytosis and phagocytosis and becoming activated by pro-inflammatory cytokines, the dendritic cells detach from the epithelium, enter lymph vessels, and are carried to regional lymph nodes. By the time they enter the lymph nodes, the dendritic cells have matured and are now able to present antigens of HIV to naive T-lymphocytes located in the the lymph nodes in order to induce adaptive immune responses.

At this point the infection has transitioned from the acute phase to the chronic phase. The chronic phase of HIV infection is characterized by viral dissemination, viremia, and induction of adaptive immune responses. The viremia (def) allows the viruses to spread and infect T4-helper lymphocytes, macrophages, and dendritic cells found in peripheral lymphoid tissues.

During the chronic phase of HIV infection, the lymph nodes and the spleen become sites for continuous viral replication and host cell destruction. During most of this phase, the immune system remains active and competent and there are few clinical symptoms. A steady state-infection generally persists where T4-lymphocyte death and T4-lymphocyte replacement by the body are in equilibrium. In a person infected with HIV, somewhere between one and two billion of these T4-cells die each day as a result of HIV infection and must be replaced by the body's lymphopoietic system (def) in the bone marrow. It is estimated that 10 billion virions are produced and cleared in an infected individual each day. However, the enormous turnover of T4-lymphocytes eventually exhausts the lymphopoietic system and it becomes unable to replace the T4-cells being destroyed. A variety of mechanisms then eventually lead to immunodeficiency.

Mechanisms of HIV-induced immunodeficiency include:

• Direct HIV-induced cytopathic effect on infected T4-lymphocytes. This can occur through:
  • Increased cell permeability as a result of gp41 expression in the host cell membrane and viral release by budding;
  • Inhibition of host cell protein synthesis as a result of viral replication within the infected cell; and
  • Fusion of infected T4-cells with numerous uninfected T4-cells resulting in syncytia (def) formation.
• Killing of HIV-infected T4-cells by cytotoxic T-lymphocytes or CTLs (def).
• Killing of HIV-infected T4-cells by antibody-dependent cytotoxicity or ADCC (def).
• Apoptosis (def) of T4-cells as a result of chronic activation by HIV and by cytokines.
• Shedding of gp120 molecules by HIV. This subsequently triggers a series of events that cause the adaptive immune system to become less and less effective, primarily by altering the normal balance of immunoregulatory T_H1 (def)and T_H2 (def) cells in the body.
• Impaired function of HIV infected macrophages (def) and dendritic cells (def).

These mechanisms will be discussed in greater detail in Unit 5 under secondary immunodeficiency.

For More Information: Secondary Immunodeficiency from Unit 6

 

To further complicate problems, during the replication of HIV the reverse transcriptase of HIV exhibits a high error rate as it transcribes the RNA genome into DNA. As a result, HIV readily mutates to become more immunoresistant, more drug resistant, and able to change the preferred cell type it is able to infect, , eg, M-tropic (def) to T-tropic (def) as shown in Fig. 2.

Progression to AIDS is marked by a viral load that progressively increases in number while the immune system weakens as a result of the destruction of increasing numbers of T4-lymphocytes (def) and the inability of the body to continually replace these destroyed cells. As will be seen in Unit 5, the loss of T4-helper lymphocytes leads to a marked decline in cells called cytotoxic T-lymphocytes (CTLs) (def), the primary cells the body's immune responses use to destroy virus-infected cells. Once a person progresses to full-blown AIDS he or she becomes susceptible to a variety of opportunistic infections by:

• bacteria such as Mycobacterium avium complex (MAC), Salmonella, and Nocardia;
• protozoa such as Cryptosporidium and Toxoplasma;
• viruses such as cytomegalovirus (CMV), herpes simplex viruses types 1 and 2 (HSV-1, HSV-2), and varicella zoster virus (VZV);
• Candida, Cryptococcus, Coccidioides, Histoplasma, and Pneumocystis.

There is also an increased incidence of tumors, such Epstein-Barr virus-associated B-cell lymphomas, other lymphomas, cervical cancer, and Kaposi’s sarcoma. Wasting syndrome and encephalopathy are also common.

 

TPS Question

 

Highly active anti-retroviral therapy (HAART) with a combination of reverse transcriptase inhibitors and protease inhibitors, as will be discussed later in Unit 4 under "Control of Viruses," has had relatively good success in both improving T4-lymphocyte levels and reducing the levels of HIV in the body - sometimes to undetectable levels. However, even with undetected levels of HIV, most infected persons continue to harbor relatively small amounts of replication-competent HIV, most likely in the resting T4-memory cells produced as a normal part of the immune responses. These infected T4-memory cells probably persist for years after antiretroviral therapy has reduced viral load below the limit of laboratory detection and could represent a pool that can keep HIV infection going or reactivate the infection. Macrophages and dendritic cells may also serve as a reservoir for HIV.

For More Information: Preview of Antiviral Chemotherapeutic Agents from Unit 4

 

Medscape article on infections associated with organisms mentioned in this Learning Object. Registration to access this website is free. HIV Infection and AIDS

 

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