HIV i-Base

Resistance 2: Key concepts: genetics, HIV structure and life cycle

2.1 Recap from previous section

The introductory reading in section 1 was general information about some of the practical issues about HIV resistance.

2.2 Introduction to section 2

For the first proper section we need to start with basics and learn about a few important concepts.

This includes an introduction to genetics, how HIV makes copies of itself (when it reproduces or replicates) and how it makes tiny mistakes each time.

2.3 Genetics

The structure of things that reproduce, grow and die is usually dependent on genetic material. This is the case for bacteria, viruses, insects, animals, a tomato, a beanstalk or a human.

This genetic material is usually the double strand of RNA called DNA (see Figure 1).

DNA is like a recipe book for how to make a new organism (tomato/human/virus etc). For humans, DNA is in cells that have a nucleus – skin cells, bone cells, brain cells, liver cells, blood cells and many others.

The genetic structure of HIV is slightly different because it is single-stranded RNA. Before it can replicate inside the nucleus of a human cell, it needs to be transformed into double stranded DNA. To do this, HIV mainly uses CD4 cells. These are a type of blood cells that are part of the immune system.

DNA is made up of a chain of chemicals called nucleotides (or bases). There are only four bases and the order of the bases determine what they do. The chain of bases are held together by a backbone of two strands of sugar and phosphate molecules. This makes the familiar double helix structure in Figure 1.

Figure 1: Simplified illustrations of DNA

a) simplified to illustrate bases and backbone

b) molecular structure of the bases and the sugar and phosphate groups that form the backbone

Source: US National Library of Medicine.

Human DNA is a chain of 3,000,000,000 bases. The four bases are abbreviated to letters: A (adenine), T (thymine), C (cytosine) and G (guanine).

The code for a human will look very similar (but is much longer):
TACCTTGAGGTGTTGAGGTGCCAAAATGGTGACCCCTTGAG

GTGCCAAAATGGTGTTGAGGTGCCAAAATGGTGACCATTGA

GGTGCC AAAATGGTGACCAAAACCATG etc (out to 3,000,000,000 letters).

Because DNA is a double strand, this is actually a double chain of 3,000,000,000 base pairs. The pairs always twin A with T, and C with G. So the chain looks like:

T A C C T T G A

I   I   I   I  I   I   I   I

A T G G A A C T etc

HIV is a similar chain, but much shorter with about 9,700 bases.

This is the recipe for HIV to replicate. If these letters change for any reason, it is like changing the the recipe. The next generation of HIV will then be slightly different.

Changes in each generation is called evolution. Evolution occurs for every living thing – for humans, tomatoes and viruses.

See Appendix 2 for more information about DNA.

2.4: Life cycles and replication

Every living thing, by definition, has a life cycle. This is repeated from generation to generation.  At it’s most basic, this includes:

  1. Early development and birth.
  2. Reproduction, perhaps many times.
  3. Death.

Replication involves passing genetic material from one generation to the next.

The life cycle for HIV is very fast. HIV in an active CD4 cell only survives for 1–2 days. Over this time, a cell is infected, the virus replicates and then the cell dies. Infected cells also signal to uninfected cells to die more quickly. In an HIV negative person, CD4 cells live for 3-4 days, so HIV causes all activated CD4 cells to live for a shorter time. However, most of the immune system is resting or asleep. HIV in a resting cell is also resting.

HIV is also very prolific–it replicates a lot! Each infected CD4 cell produces several hundred new infectious particles of HIV (called virions). A virus is called a virion when it is not inside a cell. These virions infect new CD4 cells and the cycle repeats.  When not on treatment, millions of CD4 cells become infected every day and at least 100 million new HIV virions are produced each day.

HIV has one of the highest and fastest replication rates of all viruses. It replicates a lot in a very short time.

HIV has to reproduce its genetic code which is in the form of a strand of 9,200 bases. Small mistakes in copying the genetic RNA is like print errors in a recipe. Because HIV does not have a way to proofread, mistakes are common. In every reproduction cycle it makes at least one mistake.

By comparison, human DNA replication usually has very accurate proof-reading. If it detects an error it goes back to correct it. In humans an error occurs only once in every 10-100 million bases. In humans, many changes are not important and the role of much of human DNA is not understood. Although 90% of DNA was thought to be junk more recent research thinks it may be more important and that we just have not yet understood it.

If a recipe spelled ‘sugar’ as ‘suger’ you would probably guess right and still make a good cake.

However, if it changed ‘2 eggs’ to ‘20 eggs’ it would be a mess.

With HIV, some changes are important and some make no noticeable difference. Sometimes, one change affect the way a drug works.

The lack of proof reading, together with the vast amount of new viruses produced each day, makes it likely that at least one HIV mutation will be produced in every cycle (when not on treatment).

Sometimes dual mutations may occur on the same strand of HIV. Luckily, even with so much virus being produced triple mutations relating to drug resistance rarely occur by chance.

To understand how different mutations affect drug resistance it is useful to use a different diagram for the structure of HIV. (See Appendix 5 for an illustration of the HIV genome).

This shows the genetic structure of the single strand of RNA for HIV as nine main genes. In order to picture this structure, the genetic structure of HIV RNA that shows each gene, is shown as a block, some of which overlap.

Each of these main genes plays an important role in making new HIV. You don’t need to learn the function of each gene but it is useful to know that they exist.

By comparison, the chains of nucleotides in human DNA is organised into over 20,000 genes (in 23 pairs of chromosomes).

2.5 HIV replication

The third point in this section involves combining points one and two:

i) HIV is a chain of 9,200 bases that replicates every 1–2 days.

ii) Even with a viral load of only 10,000 copies/mL, over 100 million new viruses are produced each day.

iii) Every reproduction cycle includes at least one mistake: somewhere an A could change to a C; or a G to an A etc; just by accident. HIV does not proofread. 

Before starting treatment (ie before viral load is dramatically reduced) every single base change is likely to be present. Some of these mutations cause drug resistance.

2.6 Section 2: Learning points

  • HIV is a virus made up of two single strands of genetic material, called RNA.
  • The genetic material in HIV is much shorter than human DNA. It is like comparing a pea to the Titanic.
  • The order of the four bases determines everything about the structure of an organism (whether this is a virus, a tomato or a human).
  • The lifecycle for HIV is short (only 1-2 days).
  • The natural process of replication sometimes involves slight changes to the genetic structure. These are called mutations.
  • HIV doesn’t have a way to proofread for these mutations. This means that everyday slightly different new versions of HIV are produced.
  • Often these new mutations make no difference, but some can stop an HIV drug from working.

2.7 Section 2 evaluation

Please now take a few minutes to evaluate this session online. This single page includes six short questions.

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2 comments

  1. There are people who are immune. A small fraction of people of European descent are mising a key part of the white blood cells HIV needs to infect you. These people are immune to all of the most common strains of HIV. If you get exposed to HIV, not everyone gets infected. The percentage of people who get infected is reduced if you get masive doses of HIV drugs in the first few hours after exposure.

  2. Thanks. The immune protection some people have against HIV is related to a genetic difference called delta-32 deletion in the CCR5 coreceptor. CCR5 on the surface of CD4 cells is needed by the virus to connect to the immune cells it needs to infect. People with this deletion on both sets of their chromosomes are called homozygous and have the greatest protection from HIV that uses CCR5 (called R5-tropic virus). This doesn’t guarantee protection from infection though because HIV can change the use of this coreceptor over time. So some people, usually later in infection, have virus that uses a coreceptor called CXCR4 (called X4-tropic virus). If someone with the CCR5 genetic deletion gets exposed to X4 virus, they can become infected.
    See these two articles:
    CXCR4-using HIV found in 8.5% during early HIV infection
    Case report: homozygous CCR5 delta-32 protection overcome by infection with X4 virus

    Your second point about not everyone getting infected is also true. HIV is generally a difficult virus to catch and most people who are exposed do not become infected. Risks from sexual exposure range from very low to very high depending on many factors, including viral load, the type of sex, genetics and luck. Some do though, and it only takes one exposure for an infection to occur. See this guide to sexual HIV transmission.

    Finally, using HIV drugs after exposure to reduce the chance of infection is called PEP. It doesn’t require ‘massive’ doses though. Doses for PEP use the standard doses recommended for treatment. It usually requires taking a combination of three different oral drugs daily for four weeks. The earlier PEP is started the more chance there is that it will work. See PEP, PEPSE and PrEP.