HUMAN IMMUNODEFICIENCY VIRUS (HIV)

Introduction

Human immunodeficiency virus is one of the most dangerous viruses known to humans. It is a sexually transmitted virus that causes progressive failure of the immune system. HIV targets the Helper T-lymphocytes, the main regulatory white blood cells in the human immune system. The acquired immunodeficiency syndrome caused by HIV makes the body susceptible to several opportunistic infections as well as cancers.

HIV not only causes the life-threatening immune system failure but also has profound effects on the cognitive functions and memory of a person. It can cause dementia in some patients. The memory impairments caused by HIV are being studied by the researchers.

In this article, we will discuss the structure of HIV, its transmission in humans, as well as the harmful effects caused by it. We will also talk about the cognitive and memory impairments caused by HIV. Keep reading.

Basic Structure and Properties

In this section, we will discuss the important structural and pathological properties of HIV.

Structure

HIV is an RNA enveloped virus belonging to the category of retroviruses. It has a cylindrical D-shaped core containing the genome of the virus and some enzymes. This core is surrounded by an envelope containing virus-specific glycoproteins.

The core of HIV contains two molecules of RNA associated with reverse transcriptase enzymes. A nucleocapsid surrounds the genome. This capsid is made up of p24 proteins. Except for reverse transcriptase, the other enzymes are located inside the nucleocapsid of the virus.

The nucleocapsid is surrounded by an envelope formed by two envelope glycoproteins. These glycoproteins are embedded in a lipid bilayer. The lipid bilayer is derived from the cell membrane of the infected cell.

Genome of HIV

The genome of HIV consists of two identical RNA molecules and is called diploid. The genome studies reveal that HIV has three retroviral genes and six regulatory genes.

The retroviral genes are pol, gag, and env.

  • pol genes encode several viral proteins including the reverse transcriptase enzyme
  • gag gene encodes core proteins such as the p24 protein of nucleocapsid
  • env gene encodes a precursor glycoprotein that is cleaved to form two glycoprotein present in the envelope of HIV

The six regulatory genes present in the genome regulate the various steps in the replication of the virus.

Enzymes

Three enzymes are present in the core or nucleocapsid of HIV. These are reverse transcriptase (associated with RNA), integrase, and protease (present in the nucleocapsid).

Reverse transcriptase is known as RNA-dependent DNA polymerase. This enzyme makes a copy of DNA from the viral RNA. This process is the reverse of the normal transcription process. Thus, the enzyme is called reverse transcriptase.

The integrase enzyme is responsible for the integration of viral DNA into the host DNA. Once integrated into the host DNA, it is called the proviral DNA.

Protease enzyme cleaves the precursor proteins made by the host cell to make viral polypeptides.

Natural Host of HIV

Although some other primates can also be infected with HIV in the lab, humans are the only natural host of HIV. The origin of HIV is not endogenous to humans. Some evidence exists that the chimpanzees were the source of HIV.

Important Cells infected by HIV

As mentioned earlier, HIV infects the Helper T-lymphocytes of the immune system. It mainly infects the cytotoxic helper T-lymphocytes having CD4 proteins on their plasma membranes. Other cells having CD4 proteins like macrophages and monocytes can also be infected.

Transmission

HIV is a sexually transmitted virus. It is primarily transmitted either by the sexual contact with the infected person or by the transfusion of blood. The virus can be transmitted from the infected mother to the fetus at birth through the placenta. It can also be transmitted via breast milk during breastfeeding.

More than 50% of neonatal HIV infections are due to transmission at the time of delivery. Some evidence also exists verifying the transplacental transmission of HIV.

Small amounts of HIV are also found in other body fluids such as tears and saliva. However, the viral load in these fluids is not enough to cause the infection.

The infection is caused by the transfer of HIV infected cells or free HIV particles.

People who are already suffering from some sexually transmitted diseases such as syphilis have a higher risk to get HIV. Likewise, uncircumcised men have a higher risk of getting infected with this virus.

Life Cycle

The life cycle or replicative cycle of HIV is completed in the CD4 helper T-cells. its life cycle can be divided into the following major steps;

  • Entry: The first step is the entry of the virus into the cell. The gp120 protein present in the envelope of the virus binds to the CD4 receptor proteins on the target cell. It also interacts with a chemokine protein. These protein interactions activate the gp41 protein in the envelope of HIV. The gp41 causes the viral envelope to fuse with the plasma membrane of the target cell. As a result, the core of the virus enters the target cell.
  • Reverse transcription: In the next step, the reverse transcriptase enzyme makes double-stranded DNA from the viral RNA. The newly synthesized DNA called the viral DNA migrates to the nucleus of the host cell. The viral RNA later undergoes degradation.
  • Integration: The viral DNA is integrated into the host DNA by the integrase enzyme. Multiple copies of viral DNA can be made and integrated at multiple sites of host DNA.
  • Transcription: The proviral DNA is transcribed to form viral mRNA. It encodes for the proteins needed to form the new copies of HIV.
  • Translation: In this step, the viral mRNA is translated to form polypeptides that are essential for the synthesis of nucleocapsid and envelope proteins. The new copies of enzymes are also made during this step.
  • Assembly: The proteins are assembled to form immature viral particles.
  • Cleavage of Proteins: Protease enzyme cleaves the polypeptides formed in the previous step to form viral proteins. The envelope polypeptides are cleaved by the protease present in the host cell. The cleavage takes place as the virus buds off from the host cell and indicates the mature virus.
  • Budding: The new copies of HIV thus formed fuse with the cell membrane and bud off in the form of bubbles. The lipid bilayer of the virus envelope is acquired during this phase. The cleavage and budding go on side by side.

Pathogenesis

HIV infects and kills the helper T-cells in the immune system. As a result, the cell-mediated immunity is suppressed and the person becomes susceptible to several infections and cancers.

Different theories have been proposed to explain the process by which HIV causes the death of helper T-cells. one theory suggests that HIV acts as a superantigen activating various other helper-T cells. As a result, several helper-T cells become activated and die.

Predisposition to Cancers

The patients infected with HIV have a higher incidence of certain cancers like Kaposi’s sarcoma and lymphoma. HIV does not directly cause these cancers as the HIV genes are not found in the cancerous cells. The higher susceptibility to certain cancers may be due to the loss of cell-mediated immunity. The majority of the helper T-cells are not present to destroy the early cancerous cells. Decreased immunity leads to full-blown cancer.

Predisposition to Infections

HIV also targets and kills the Th-17 cells, a subset of CD4 helper T-cells. These cells have a major role in providing immunity at the mucosal surfaces mainly in the gastrointestinal tract.

Th-17 cells provide immunity to infections by attracting neutrophils at the site of infection. These cells are destroyed early in HIV infection. The loss of Th-17 cells predisposes the infected individual to the blood-borne infections of the normal flora present in the gut. Gastrointestinal infections are also very common in such individuals.

Infection of Brain cells

HIV infection is not only limited to the helper T-cells. It also infects the CD4 cells present in the brain such as monocytes and macrophages. The infected cells fuse to form giant cells.

The giant cells and abnormal glial cells are produced. These can cause several CNS symptoms as discussed in another heading of this article.

The giant cells produced as a result of HIV infection are not able to perform their function. Thus, they die immediately producing CNS symptoms. Cell death may also be attributed to the action fo cytotoxic CD8 cells. These cells are activated as an immune response to HIV Infection and are destined to kill the infected cells.

Immune Response to HIV infection

The immune response to HIV infection is mediated by the activation of CD8+ cells. These cells respond fast and can limit the early infection for years. However, the failure of cytotoxic response at some stage of life causes the clinical symptoms of AIDS. Cytotoxic T-cells lose their effectiveness as a large number of helper T-cells have died. The helper T-cells play a supportive role in the action of cytotoxic T-cells.

Latent Infection

As mentioned earlier, the immune response by the cytotoxic T-cells can limit the HIV infection for years. Latent infection can occur in some individuals in which no new HIV is produced as the CD4 cells are at rest. The HIV genome is integrated into the memory cells.

The latent period can last for months to years. But once the CD4 cells become activated, new HIV can be produced from the genome in the memory cells.

Although certain drugs can decrease the formation of new HIV, a person once infected by HIV remains infected for his entire life.

Mechanisms to Evade Immune Response

There are three mechanisms by which HIV can evade the immune system. These are as follows;

  • Integration of viral DNA into the host genome causes persistent infection
  • There is a higher rate of mutations in the env gene of HIV
  • HIV produces proteins that downregulate the MHV-1 protein necessary for the action of cytotoxic T-cells

Clinical Features

The clinical finding of HIV can be divided into three stages; an early stage, latent stage, and the immune deficiency stage.

Early or Acute Stage

This stage begins 2 to 4 weeks after infection with HIV. The patient presents a picture of fever, sore throat, lethargy, and lymphadenopathy. A rash is also seen on trunk, legs, arms, and back. A decreased white blood cell count can be seen in the blood picture.

During this stage, the disease is highly transmissible. The acute stage usually resolves in two weeks. The end of the acute stage is characterized by a high count of cytotoxic CD8 cells as an immune response.

Antibodies against HIV start appearing in the blood around 10 to 14 days after infection. The antibody test comes positive 3 to 4 weeks after the initial infection. The false-negative serological tests are common in the early days despite the fact the infection exists.

Latent Stage

The middle or latent stage is characterized by a long latent period. The latent period usually lasts for 9 to 11 years. During this stage, the patient remains asymptomatic and the viral load in blood is also very low. A large amount of HIV is still produced by the lymphocytes but they remain sequestered in the lymph nodes. Thus, the virus is still active and is not in the latent state.

AIDS-related complex (ARC) is a syndrome that can occur during the latent period of HIV. It is characterized by fatigue, weight loss, fever, and lymphadenopathy.

Immune Deficiency Stage

The last stage of HIV infection is characterized by acquired immunodeficiency syndrome (AIDS). During this stage, the helper CD4 cell count decreases to a significantly low quantity. As a result, the patient becomes susceptible to several opportunistic infections.

The most important manifestations of AIDS are pneumonia and Kaposi’s sarcoma. Other viral and bacterial infections such as herpes infection, tuberculosis, toxoplasmosis are also seen.

AIDS patients also have dementia and some other neurologic problems either caused by HIV infection of the brain or other opportunistic infections.

Dementia in HIV

In the late stage of HIV infection, the patients may develop dementia known as HIV dementia complex or AIDS dementia complex. It results in the cognitive impairment of the affected person. The person feels trouble in thinking, understanding, and remembering things. The important features of HIV related dementia are forgetfulness, loss of memory and irritability, etc.

Certain antiviral drugs that limit the progression of HIV can prevent patients from HIV associated dementia.

HIV associated Neurologic Symptoms

Besides dementia, some other neurologic symptoms are also associated with HIV. These are either caused by damage to the macrophages in the brain by HIV or due to opportunistic infections. Cytomegala infection in HIV can cause cognitive decline. It also impacts physical control, vision, and hearing of the infected person.

HIV can directly damage the nerves throughout the body causing pain and weakness.

Treatment and Prevention

The main goal in the treatment of HIV is to limit the viral load and to restore the immunological functions of the body. Certain antiviral drugs have proved to be highly effective in the management of HIV. Although no drug can cure HIV, immune deficiency can be prevented by using certain drugs. These include reverse transcriptase inhibitors and protease inhibitors.

No vaccine is available for the prevention of HIV. Safe sex and safe blood transfusions can prevent HIV. Antiretroviral therapy should be given to the infected mother and neonates to limit the cases. Infected mothers should also not breast feed their infants.

Summary

HIV is a retrovirus that infects the helper T-cells and other cells having CD4 receptors on the plasma membrane.

HIV is an RNA enveloped virus. The cylindrical core is surrounded by an envelope made up of glycoproteins and a lipid bilayer.

The genome consists of two identical RNA molecules, each having three retroviral genes and six regulatory genes.

Reverse transcriptase, protease, and integrase are the enzymes present in the core of the virus.

Humans are the only natural hosts of HIV.

The life cycle of HIV consists of the folwing stages;

  • Entry into the host cell
  • Reverse transcription and integration of viral DNA into host DNA
  • Transcription of viral DNA to form viral RNA
  • Synthesis of viral proteins
  • Assembly of the proteins to form new copies of the virus
  • Maturation of the virus and budding from the host cell

HIV is transmitted during unprotected sex or unsafe blood transfusion. Transmission from mother to baby can occur during delivery or via breast milk.

It infects the helper T-cells and decreases the cell-mediated immunity, making the person susceptible to opportunistic infections as well as cancers.

Cytotoxic T-cells are produced as an immune response to the acute HIV infection. These cells can limit the spread of infection for some years.

HIV also uses certain mechanisms to escape the immune system barriers in humans.

The clinical features are described in three stages of the infection; acute, latent, and late stage.

Dementia and other neurological signs are also seen in HIV patients due to some opportunistic infections.

Certain antiviral drugs can limit the spread of the infection. Some precautionary measures should be adopted to prevent HIV.

References

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